The mechanisms of epigenetic inheritance: how diverse are they?

Biol. Rev. (2018), pp. 000–000. 1
doi: 10.1111/brv.12429
The mechanisms of epigenetic inheritance:
how diverse are they?
Oleg N. Tikhodeyev∗
Department of Genetics & Biotechnology, Saint-Petersburg State University, Saint-Petersburg 199034, Russia
ABSTRACT
Although epigenetic inheritance (EI) is a rapidly growing field of modern biology, it still has no clear place in
fundamental genetic concepts which are traditionally based on the hereditary role of DNA. Moreover, not all
mechanisms of EI attract the same attention, with most studies focused on DNA methylation, histone modification,
RNA interference and amyloid prionization, but relatively few considering other mechanisms such as stable inhibition
of plastid translation. Herein, we discuss all known and some hypothetical mechanisms that can underlie the stable
inheritance of phenotypically distinct hereditary factors that lack differences in DNA sequence. These mechanisms
include (i) regulation of transcription by DNA methylation, histone modifications, and transcription factors, (ii) RNA
splicing, (iii) RNA-mediated post-transcriptional silencing, (iv) organellar translation, (v) protein processing by truncation,
(vi) post-translational chemical modifications, (vii) protein folding, and (viii) homologous and non-homologous protein
interactions. The breadth of this list suggests that any or almost any regulatory mechanism that participates in gene
expression or gene-product functioning, under certain circumstances, may produce EI. Although the modes of EI are
highly variable, in many epigenetic systems, stable allelic variants can be distinguished. Irrespective of their nature, all
such alleles have an underlying similarity: each is a bimodular hereditary unit, whose features depend on (i) a certain
epigenetic mark (epigenetic determinant) in the DNA sequence or its product, and (ii) the DNA sequence itself (DNA
determinant; if this is absent, the epigenetic allele fails to perpetuate). Thus, stable allelic epigenetic inheritance (SAEI)
does not contradict the hereditary role of DNA, but involves additional molecular mechanisms with no or almost no
limitations to their variety.
Key words: epigenetic inheritance, DNA methylation, histone modification, chromatin remodelling, bistable gene
networks, hereditary prions, RNA interference, self-splicing, trans-generation memory, body-to-body information
transfer.
CONTENTS
I. Introduction .............................................................................................. 2
II. Epigenetic hereditary factors ............................................................................. 3
III. Modes of EI .............................................................................................. 4
IV. Mechanisms of SAEI ..................................................................................... 4
(1) DNA methylation/demethylation .................................................................... 4
(2) Histone modifications ................................................................................ 5
(3) Positive feedback using transcription factors .......................................................... 6
(4) Post-transcriptional silencing through RNA interference ............................................. 6
(5) Stable inhibition of plastid translation ................................................................ 6
(6) Positive feedback through protein phosphorylation ................................................... 7
(7) Positive feedback through protein truncation ......................................................... 7
(8) Switch of protein conformation from native to amyloid .............................................. 8
(9) Reproducible non-homologous protein interaction ................................................... 8
(10) Reproducible differences in cortex structure .......................................................... 9
(11) Other possible mechanisms ........................................................................... 9
* Address for correspondence (Tel: +7 (921) 899-87-71; Fax: +7 (812) 328-15-90; E-mail: tikhodeyev@mail.ru.
Biological Reviews (2018) 000–000 © 2018 Cambridge Philosophical Society

2 Oleg N. Tikhodeyev
V. What do mechanisms of SAEI have in common? The bimodularity principle ........................... 11
VI. Advantages of the bimodularity principle ................................................................ 14
VII. Perspectives .............................................................................................. 14
VIII. Conclusions .............................................................................................. 15
IX. Acknowledgments ........................................................................................ 15
X. References ................................................................................................ 16
XI. Supporting Information .................................................................................. 19
I. INTRODUCTION
In the first half of the 20th century, when the chromosome
theory of inheritance had been established, the chemical
nature of genetic material remained unknown. Proteins and
DNA, both key chromosome components, were considered
as candidates for this role, but proteins were preferred due to
the higher complexity of their chemical structure (Koltzoff,
1928; Mirsky, 1943).
After the genetic role of DNA had been demonstrated
(Avery, MacLeod, & McCarty, 1944; Hershey & Chase,
1952), the chromosome theory of inheritance was implicitly
transformed into the DNA theory of inheritance (Hershey,
1970; Portin, 2014). The core of this theory was DNA
duplication using Watson–Crick base complementation
(Watson & Crick, 1953). Revealing the molecular nature
of point mutations (Ingram, 1957; Sarabhai et al., 1964;
Yanofsky et al., 1964) gave additional support to the DNA
theory. So, by the mid-1970s it was strongly believed that all
hereditary factors are DNA sequences.
Exceptions to this rule, such as paramutations in maize
(Brown & Brink, 1960) or cortical inheritance in ciliates
(Beisson & Sonneborn, 1965) were known from the mid-20th
century; however, they were considered to be exotic oddities
that did not affect the validity of the DNA theory. Only
in the 1990s, when numerous examples of inheritance
without variation in DNA sequence had been found in many
species (see Section IV), such ‘exceptions’ were accepted as a
widely occurring phenomenon. This phenomenon has been
called epigenetic inheritance (EI) (Jablonka & Lamb, 1995;
Russo, Martienssen, & Riggs, 1996; see online Supporting
information, Appendix S1 for the etymology of this term).
The concepts of EI have a long history. The basic idea
that genes can produce hypothetical products (so-called
‘plasmogenes’), which are able to persist in the cytoplasm and
affect the phenotype of subsequent progeny, was suggested by
Sewall Wright in the 1940s (Wright, 1945), before the nature
of genes was known. This idea was later modified by Joshua
Lederberg (1958) who proposed distinguishing several types
of information, including nucleic and epinucleic, of which the
latter was responsible for somatic cell speciation. However,
at that time, the molecular basis for epinucleic information
remained elusive, and this term was not accepted.
The idea of plasmogenes gained popularity in the 1960s
following studies on cytoplasmic inheritance of the killer
phenotype in Paramecium. It was proposed that the killer
phenotype was mediated by invisible cytoplasmic particles
(‘metagons’) produced in the presence of specific genes; after
removal of these genes, the metagons were thought to be
passively distributed among the daughter cells for numerous
divisions (Gibson & Sonneborn, 1964). For several years,
these metagons were believed to be self-replicable RNAs,
but later the killer phenotype was demonstrated to be caused
by specific endosymbiotic bacteria and the metagon theory
was rejected (see Schrallhammer, 2010).
In the mid-1960s, John Griffith suggested that at least
some cases of EI might be a result of self-sustaining loops
produced by regulatory proteins like transcription factors
(Griffith, 1967). This scheme was proposed for scrapie but
appeared to be inappropriate for it. However, since scrapie
infection particles were shown to be DNA- and RNA-free,
the idea of protein-only inheritance has arisen.
The first successful attempt to link EI with particular
genes and gene products was accomplished by Rustem
Tchuraev. He introduced the concept of an ‘epigene’, a
hereditary unit in which some part of information is kept,
reproduced, and transmitted to the progeny beyond the
primary structure of DNA (Tchuraev, 1975; for a review,
see Tchuraev, 2006). This concept was realized in vivo as a
digenic cross-regulated unit (Fig. 1) (Tchuraev et al., 2000;
Tropynina et al., 2002) with numerous modifications also
suggested (Tchuraev, 2006).
Eva Jablonka and co-workers carried out an extensive
analysis of various types and mechanisms of EI (for reviews,
see Jablonka & Lamb, 1995, 2002, 2005; Jablonka & Raz,
2009). They considered EI in two senses: narrow and
broad. The narrow sense covers all kinds of cellular EI:
epigenetic information is represented by specific molecular
complexes that can be transmitted from one cell to another
(see Jablonka & Lamb, 2005). Such transmission can
take place via several mechanisms including chromatin
marking, RNA-mediated inheritance, structural inheritance,
and self-sustaining feedback loops. Each mechanism of
cellular EI is referred to as an epigenetic inheritance system
(EIS). This system is multifactorial in which both DNA
and specific epigenetic marks are important in the resulting
effects, and different EISs may interact with each other.
The broad sense embraces cellular EI and all types of
body-to-body information transfer through developmental
interactions between mother and embryo, social learning,
and symbolic communications (Jablonka & Lamb, 2005,
2006). No certain mechanisms for body-to-body information
transfer are yet described, but in neuro-epigenetics it is
proposed that at least some of them might relate to those of
cellular EI (see Saab & Mansuy, 2014).

Mechanisms of epigenetic inheritance 3
Fig. 1. A digenic unit with negative cross-regulation through competition between two transcription factors (the general idea is
similar to Delbruck, 1949). Two open reading frames, ORF1 and ORF2 (black lines), are regulated by two promoters, P1 and P2
(large grey arrows), respectively. P1 and P2 may be partially overlapping (as shown) or separate. ORF1 encodes transcription factor
TF1, which represses P2. In turn, ORF2 encodes transcription factor TF2, which represses P1. As a result, ORF1 and ORF2 cannot
be expressed simultaneously.
In the 1990s, the first examples of hereditary prions were
described (Wickner, 1994; Derkatch et al., 1996; Coustou
et al., 1997), resulting in a revival of the protein-only
hypothesis in which specific protein states were seen
as atypical hereditary factors responsible for so-called
protein-based inheritance (see Chernoff, 2007; Harvey,
Chen, & Jarosz, 2018). Thus, some geneticists consider
hereditary prions to be protein genes (Wickner et al., 2004,
2010), and see protein-based inheritance as an alternative
to chromosome-based inheritance (Harvey et al., 2018).
A contrasting view on hereditary prions was introduced
by Sergei Inge-Vechtomov, who considered them as
conformational (‘second order’) templates additional to
DNA (‘first order’) ones (Inge-Vechtomov, 2013, 2015).
However, this does not apply to non-amyloid hereditary
prions which are reproduced via self-sustaining loops without
conformational templates.
EI can take place by various mechanisms (Jablonka &
Raz, 2009; Tikhodeyev, 2016). This review briefly describes
all known mechanisms of EI and speculates on some other
possibilities.
II. EPIGENETIC HEREDITARY FACTORS
The number of known epigenetic hereditary factors (EHFs)
is very high, and many new ones are revealed annually.
They display dramatic variety both in molecular nature and
in modes of inheritance. However, some generalizations are
possible. In particular, among the vast diversity of EHFs,
allelic EHFs can be identified.
The term ‘allele’ is traditionally used for DNA sequences
but can also be applied to many EHFs. Indeed, EHFs
produced by DNA methylation were called ‘epialleles’
40 years ago (Kermicle, 1978); they are allelic to the wild-type
states of the corresponding DNA sequences. Some authors
(Jablonka & Lamb, 1995) suggested expanding this term to
cover all chromatin-related heritable forms of a gene with
an unchanged DNA sequence. Moreover, different variants
of the same hereditary prion (see Sections IV.8, V, VI) were
recently considered to be prion alleles (Tikhodeyev, Tarasov,
& Bondarev, 2017). The list of allelic EHFs also includes
lyonized and active X chromosomes in some cell lineages
in mammalian females (Clerc & Avner, 2011), alternative
expression states of bistable networks in bacteria (Gardner,
Cantor, & Collins, 2000; Tchuraev et al., 2000), irreversibly
inhibited and normal plastid translation in plants (Zubko
& Day, 1998), and alternative orientations of a particular
ciliary row in ciliates (Beisson, 2008), among others. Such
allelic EHFs will be further termed ‘allelic states of an
epigene’ or in short ‘epigene alleles’. We derive this term
from the word ‘epigene’ (see Section I). An epigene allele
(EA) is not to be confused with ‘epiallele’, which has a
significantly narrower definition (see Section VI). Organisms
possessing two identical or two different EAs can be referred
to as ‘epigene homozygotes’ or ‘epigene heterozygotes’,
respectively.
An EA lacking the epigenetic mark(s) specific to a given
mechanism of EI will be further described as an ‘epigenetic
null-allele’ (ENA). As a canonical null-allele (absence of the
entire DNA sequence of a certain gene) is a member of
multiple allelic variants of that gene, similarly each ENA
is a member of a set of EAs. For example, a completely
non-methylated state of a certain DNA region will represent
an ENA that is allelic to a variety of hyper-, normally, and
poorly methylated states of the same region. In budding
yeast, different variants of the amyloid prion [PSI+
] (see
Sections IV.8, V, VI) are allelic to each other and also to the
[psi−
] states, in which all the molecules of the corresponding
protein (the eukaryotic translation release factor Sup35p)
possess the native, i.e. non-amyloid, conformation. Here,
any [psi−
] state is an ENA.
Meanwhile, ENAs are not clear equivalents of canonical
null-alleles. First, most ENAs are potentially reversible, either
spontaneously or under induction (see Section IV). Second,
for any particular ENA, we do not imply that all epigenetic
marks are absent; for instance, the [psi−
] state (absence
of SUP35p prion conformation) can be combined with
the methylated state of the SUP35 gene. This hereditary
unit is represented by the prion ENA and the epiallele

simultaneously. Thus, for each particular ENA, we take into
account only a single mechanism of EI; hence, multifactorial
ENAs can also occur. For example, the [psi−
] state of SUP35p
combined with the non-methylated state of SUP35 could be
considered as a double ENA.
Even multifactorial ENAs are not to be confused with
canonical ‘DNA-only’ alleles. Indeed, for any particular
ENA, some stable epigenetic marks may be known for the
corresponding gene and/or its product(s) but are absent
in this particular case. By contrast, canonical ‘DNA-only’
alleles are characteristic to the genes without stable epigenetic
differences in either the DNA sequences or their products.
III. MODES OF EI
EI covers highly heterogenic phenomena. Some epigene
homo- and heterozygotes are stable (Kakutani et al., 1999;
Clerc & Avner, 2011), while others undergo complete or
partial erasure (Richards, 2006). Some epigene heterozygotes
are subject to paramutation: one of two EAs, usually an ENA,
undergoes predictable epigenetic conversion and becomes
like another in its manifestation (see Tuite, 2015; Hollick,
2016).
EAs vary strongly in their modes of inheritance. Some
EAs, like the BAL epiallele in Arabidopsis thaliana, behave
as Mendelian factors: they show stable inheritance both
mitotically and meiotically, and can be even mapped by
classical linkage analysis (Kakutani et al., 1999). The r’
epiallele in maize produced by paramutation is relatively
stable in mitotic divisions, but gradually weakens in
sexual generations (Styles & Brink, 1969; Arteaga-Vazquez
& Chandler, 2010). Lyonization of X chromosomes in
mammalian females shows stable inheritance in mitoses,
but is not transmittable through meiosis (Clerc & Avner,
2011); a similar characteristic is seen in the heritable
variant of the C prion in Podospora anserina (Silar et al.,
1999). Dauermodification induced by maternal starvation
in Daphnia (the mechanism is unknown) is not transmittable
through meiosis, and progressively weakens in mitotic
parthenogenetic generations (Woltereck, 1919).
Under specific conditions, the same EA may display
dramatically different and even exotic modes of inheritance.
One of the best examples is the fate of the amyloid
prion [PSI+] in various DNA sequence backgrounds. In
the wild-type background, [PSI+
] behaves as a dominant
non-Mendelian hereditary factor with relatively stable
mitotic and meiotic inheritance (Cox, 1965). The key genes
required for [PSI+
] perpetuation are SUP35 and HSP104.
The first encodes the prion protein itself, and the second
codes for a chaperone (heat shock protein 104) which cleaves
the [PSI+
] aggregates into fragments, thus ‘seeding’ the next
generation of the prion (see Liebman & Chernoff, 2012).
When the Sup35p N-domain is absent (see Section V), the
[PSI+
] aggregates fail to elongate; however, they are still
cleaved by Hsp104. As a result, [PSI+] is progressively
diluted in cell divisions until it is lost, but can be rescued
if transmitted to the wild-type background (Cox, Ness,
& Tuite, 2003). In the absence of Hsp104 activity, the
[PSI+
] aggregates are not cleaved, and no ‘prion seeds’
are produced (Paushkin et al., 1996). Meanwhile, the [PSI+
]
aggregates continue to elongate due to incorporation of
the newly synthesized Sup35p molecules. In budding yeast,
the buds are comparably small; so, the extra-long [PSI+]
aggregates remain in the mother cell and are not transmitted
to the progeny (Byrne et al., 2009). Moreover, since the
mother cell is limited in its ability to divide, the initial
[PSI+
] strain eventually becomes [psi−
]. Thus, depending
on the conditions, the same EA can either show stable
heritability, progressive reduction over generations, or even
non-transmittability to the progeny.
Finally, some EHFs are precisely duplicated in each
cell cycle and show stable inheritance both mitotically and
meiotically, but have no allelic variants. This is typical of
centriole inheritance (Wilson, 2008). Moreover, membranes
are also inherited in each cell cycle (Cavalier-Smith, 2004),
but they are highly dynamic, with no clear allelic variants.
Thus, the term ‘allele’ can be applied to many but not
all EHFs (this term implies the existence of at least two
clearly distinct alternative hereditary states; see Bateson,
1902; Johannsen, 1909).
The field of EI is too wide to include all the underlying
mechanisms herein. We thus concentrate on examples where
clear allelic variants exist, and such variants show stable
inheritance (i.e. the corresponding phenotypes are repro-
duced at least in 10 generations of multicellular organisms or
in at least 100 cell divisions). Our goal therefore is to review
the diversity and general principles of the mechanisms
underlying stable allelic epigenetic inheritance (SAEI), and
to draw particular attention to those that are rarely discussed.
IV. MECHANISMS OF SAEI
Ten mechanisms of SAEI are known at present (Table 1).
Their general feature is an ability to perpetuate a particular
regulatory state via either replication or reconstruction of
specific epigenetic marks. In the first case, the regulatory
state is continuously reproduced within a cell and its progeny
via some template principle or positive feedback loop; in
the second case, this state is not transmitted directly to the
progeny, but is reconstructed under specific conditions (see
Section VII).
Some of the mechanisms of SAEI, e.g. DNA methylation/
demethylation and histone modifications, have been
extensively reviewed elsewhere (see Richards, 2006; Allis
et al., 2007; Vanyushin & Ashapkin, 2011; Cheedipudi,
Genolet, & Dobreva, 2014), and therefore are only
mentioned here in brief.
(1) DNA methylation/demethylation
The phenomenon of in vivo DNA methylation is found in
many prokaryotes and eukaryotes. It is involved in vital

Table 1. Mechanisms of stable allelic epigenetic inheritance (SAEI) described to date
Mechanism Heritable effect Example Reference
DNA methylation/demethylationa
Phase variation Escherichia coli Braaten et al. (1994)
Inheritance of methylated ori Caulobacter crescentus Marczynski & Shapiro (2002)
Epimutations Arabidopsis thaliana Kakutani et al. (1999)
Transcriptional silencing Neurospora crassa Martienssen & Colot (2001)
Genomic imprinting Homo sapiens Hayward et al. (1998)
X chromosome inactivation Mus musculus Gribnau & Grootegoed (2012)
Paramutations Zea mays Arteaga-Vazquez & Chandler
(2010)
Histone modificationsa
Dose compensation Drosophila melanogaster Lucchesi et al. (2005)
Vernalization A. thaliana Bastow et al. (2004)
Positive feedback using transcription factors Bistable gene networks E. coli Tchuraev et al. (2000)
Post-transcriptional silencing through RNA
interference
Heritable effects of starvation Caenorhabditis elegans Rechavi et al. (2014)
Stable inhibition of plastid translation Maternally inherited albino
phenocopies
Nicotiana tabacum Zubko & Day (1998)
Positive feedback through protein
phosphorylation
Prion C Podospora anserina Kicka et al. (2006)
Positive feedback through protein truncation Prion [β+] Saccharomyces cerevisiae Roberts & Wickner (2003)
Switch of protein conformation from native to
amyloid
Prion [PSI+] S. cerevisiae Derkatch et al. (1996)
Reproducible differences in protein
quaternary structure
Prion [GAR+
] S. cerevisiae Brown & Lindquist (2009)
Reproducible differences in cortex structure Cortical inheritance Paramecium sp. Beisson (2008)
a
These mechanisms can be guided by specific proteins and/or small RNAs.
biological processes such as DNA restriction/modification,
mismatch repair, cell division, regulation of gene expression
and transposon migration (Fedoroff, 1995; Marczynski &
Shapiro, 2002; Marinus, 2010; Smith & Meissner, 2013;
Adalsteinsson & Ferguson-Smith, 2014; Loenen & Raleigh,
2014; Nakamura et al., 2014).
Inheritance of DNA methylation state has been described
in many species, including bacteria (Casadesus & Low, 2006),
plants (Allis et al., 2007), animals (Vanyushin & Ashapkin,
2011; Adalsteinsson & Ferguson-Smith, 2014), and some
fungi (Rountree & Selker, 2010; Mishra, Baum, & Carbon,
2011). The key mechanism underlying this inheritance
is post-replicative methylation of a new DNA strand by
maintenance methylases, in which the state of an old DNA
strand is used as a template (see Casadesus & Low, 2006;
Allis et al., 2007; Vanyushin & Ashapkin, 2011).
In prokaryotes, DNA methylation states can show stable
inheritance over thousands of cell generations (Braaten
et al., 1994; Marczynski & Shapiro, 2002) and can be
horizontally transferred through conjugation (Shin, Lin,
& Lim, 2016). In eukaryotes, DNA methylation states
are usually transmitted only mitotically, apparently due
to efficient DNA demethylation during meiosis (see Allis
et al., 2007; Vanyushin & Ashapkin, 2011). However, such
demethylation can be incomplete, thus resulting in epialleles
which can be transmitted meiotically (Cubas, Vincent, &
Coen, 1999; Kakutani et al., 1999; Manning et al., 2006).
Notably, some epialleles induced by DNA hypomethylation
in A. thaliana display clear Mendelian inheritance for at
least a dozen sexual generations, and can be mapped
by recombination analysis (Kakutani et al., 1999). These
epialleles are, with regard to their mode of inheritance,
indistinguishable from classical gene mutations.
Heritable DNA methylation can be guided by specific
proteins (see Marczynski & Shapiro, 2002) or small RNAs
(see Hollick, 2016; Lebedeva, Tvorogova, & Tikhodeyev,
2017). Some epialleles of this origin are paramutagenic, i.e.
induce paramutations (see Hollick, 2016).
(2) Histone modifications
Many types of histone modifications are known (Strahl &
Allis, 2000; Turner, 2005). They are crucial for chromosome
architecture, and affect chromosome stability, the cell cycle,
DNA repair and gene expression (see Jenuwein & Allis,
2001; Samel et al., 2012; Ma, Kanakousaki, & Buttitta, 2015;
Turinetto & Giachino, 2015).
Inheritance of histone modifications is based on mecha-
nisms that use the histone modification patterns of a parental
chromosome as a template for chromatin modelling of the
daughter chromosomes. Although many details, including
the principle of inheritance (replication or reconstruction),
remain unclear (see Cheedipudi et al., 2014), several key
participants are known. For example, in animals and plants,
inheritance of H3K27me3 is mediated by the Polycomb
group complex 2 (Cao et al., 2002) or its homologs (Mozgova,
Kohler, & Hennig, 2015). Another mechanism, which
reproduces the methylated lysine 9 of histone H3 (H3K9me)
in mammals, involves the DNA methyltransferase (Dnmt1),
euchromatic histone-lysine N-methyltransferase 2 (G9a) and
RING-finger type E3 ubiquitin ligase (Uhrf1) proteins (Zhu

& Reinberg, 2011). Small RNAs also participate in these
mechanisms (see Moazed, 2009; Heo & Sung, 2011; Guérin,
Palladino, & Robert, 2014; Lebedeva et al., 2017).
Most EAs determined by histone modifications show stable
inheritance only mitotically. In multicellular organisms, such
inheritance can take place in some cell lineages, as in the case
of X chromosome histone acetylation in animals (Lucchesi,
Kelly, & Panning, 2005), or in vegetative generations, as
for H3K27me3 in vernalized plants (Jones & Sung, 2014).
It is also typical of unicellular eukaryotes like budding and
fission yeasts (Moazed, 2011; Allshire & Ekwall, 2015). The
inability of histone modification patterns to be transmitted
meiotically is thought to be due to chromatin remodelling
and disassembly of chromatin marking complexes during
meiosis (Iwasaki, 2015). However, rare examples of meiotic
transmission are known. For instance, in the elf6–5 mutant
of A. thaliana, the H3K27me3 EA induced by vernalization
is transmitted to the next sexual progeny (Crevillen et al.,
2014). Meiotic transmission of histone modification pattern
is also known in Caenorhabditis elegans (Greer et al., 2014).
Thus, depending on the conditions, this mechanism can lead
to different modes of EI.
(3) Positive feedback using transcription factors
Examples of transcriptional positive feedback have been
known since the 1960s (see Monod & Jacob, 1961).
However, they were usually described in terms of
regulation or multistability, rather than inheritance (Ptashne,
1992; Laurent & Kellershohn, 1999). The suggestion
that transcription factors could have a hereditary role
was proposed 50 years ago by John Griffith (1967) and
subsequently developed in 1975 by Rustem Tchuraev (for
a review, see Tchuraev, 2006) who proposed a digenic unit
with negative cross-regulation through competition between
two transcription factors, TF1 and TF2 (Fig. 1). This unit
displays two alternative states of expression – either TF1 or
TF2 is synthesized depending on the prevailing transcription
factor – and the chosen state is transmitted to daughter cells.
Thus, for the same DNA sequence background, two allelic
phenotypes with stable inheritance can exist.
Tchuraev’s idea was verified experimentally in a bacterial
engineered digenic unit comprising Ptrc-cI, the Ptrc promoter
fused with the cI gene, and PL-lacI, the PL promoter fused
with the lacI gene. The protein encoded by cI negatively
regulates PL, and the protein encoded by lacI negatively
regulates Ptrc; as a result, this digenic unit displays negative
cross-regulation and provides stable inheritance of a chosen
EA (cI repressor or lac repressor synthesis) for several
hundreds of cell divisions (Gardner et al., 2000; Tchuraev
et al., 2000; Tropynina et al., 2002). Notably, if an initial cell
possesses or lacks both transcription factors simultaneously,
the unit makes a random decision and retains the chosen EA
in further generations (Tchuraev, 2006).
Random events at the transcriptional level leading to
heritable differences were also described for the lac bistable
network in Escherichia coli (Gordon et al., 2009). In the absence
of an inducer, the lac operon is inhibited by the lac repressor.
However, due to intrinsic noise (the lac repressor is generally
synthesized at very low rate, and its amount in different cells
varies stochastically), the proteins encoded by the lac operon
can be transiently produced at the single-molecule level (Cai,
Friedman, & Xie, 2006). One of these proteins is galactoside
permease which transports inducers into the cell. An inducer
can then be transported into the cell by the ‘illegitimate’
galactoside permease molecule, inactivates the lac repressor
and switches the operon from the OFF to ON state. As
a result, the cell synthesizes more galactoside permease,
transports more inducer and thus retains the ON state while
inducers are present. In the presence of low concentrations of
the non-metabolizable inducer thio-methylgalactoside, the
initial population of OFF cells stochastically subdivides into
two stably heritable allelic variants (OFF and ON), and ran-
dom transcriptional errors in lac repressor synthesis increase
the frequency of the OFF to ON switch (Gordon et al., 2009).
In contrast to Tchuraev’s digenic unit, this scheme
includes a single transcription factor and requires specific
environmental conditions: the concentration of an inducer
must be sufficient to trigger the switch in some but not all
OFF cells producing the ‘illegitimate’ galactoside permease
(if the concentration is too low all cells do not switch, and if it
is too high all cells eventually become ON). Both systems are
able to lead to SAEI in binary divisions; whether a chosen
EA can be transmitted via conjugation is not known.
(4) Post-transcriptional silencing through RNA
interference
A substantial role of small RNAs in the mechanisms of
SAEI has been demonstrated in numerous species (see Allis
et al., 2007; Houri-Zeevi & Rechavi, 2017). As usual, such
RNAs participate in guiding chromatin modification and/or
DNA methylation/demethylation, and thus regulate gene
expression at the transcriptional level (Moazed, 2009; Heo
& Sung, 2011; Guérin et al., 2014; Hollick, 2016; Lebedeva
et al., 2017). However, in several cases, the role of small RNAs
likely does not relate to chromatin marks. For example, the
small 22G RNA induced by starvation in C. elegans interferes
with a set of transcripts to cause post-transcriptional silencing
of some metabolic genes (Rechavi et al., 2014). This RNA
is transmitted to the progeny for at least three generations,
and seems to be self-propagated, thus the silencing appears
to be heritable. Although the details of these processes
are unknown (see Houri-Zeevi & Rechavi, 2017), it is
possible that inherited post-transcriptional silencing through
self-propagation of specific small RNAs could be a potential
mechanism of SAEI.
(5) Stable inhibition of plastid translation
Plant cells possess three types of ribosome-containing com-
partments: cytoplasm, mitochondria and plastids. Plastids
are evolutionary descendants of ancient endosymbiotic
cyanobacteria; their ribosomes are similar to those of
prokaryotes and include about 60 different proteins and four
types of ribosomal RNAs (rRNAs) (Tiller & Bock, 2014). The

genes for these proteins must have originally been located in
the plastid genome, but many have since transferred to the
host nucleus. As a result, the genes encoding plastid ribo-
somal proteins (PLRPs) are now shared between the plastid
and nuclear genomes (Harris, Boynton, & Gillham, 1994),
while genes encoding plastid rRNAs have retained their
initial location in the plastid genome (Tiller & Bock, 2014).
The components of plastid ribosomes are synthesized
in three steps. First, the nuclear-encoded PLRPs are
produced on cytoplasmic ribosomes and transported into
plastids. Second, the plastid rRNAs are synthesized by the
nuclear-encoded RNA-polymerase (NEP) (Kapoor, Suzuki,
& Sugiura, 1997; Liere et al., 2004), in a process which does
not depend on plastid translation. Third, the plastid-encoded
PLRPs are produced, which requires pre-existing functional
plastid ribosomes. If plastid translation is inhibited by
antibiotics, the third step does not take place and the cell lacks
functional plastid ribosomes; these cannot be restored even
following antibiotic removal (Zubko & Day, 1998, 2002).
Such cells are unable to produce plastid-encoded proteins
and acquire an albino phenotype due to feedback repression
of chlorophyll synthesis.
This phenotype is stably inherited in vegetative genera-
tions. Moreover, since the plastids are usually inherited in
plants only maternally (Day & Ellis, 1984; Reboud & Zeyl,
1994), the albino phenotype induced by antibiotics shows
both mitotic and maternal meiotic inheritance in both
dicots (Zubko & Day, 1998) and monocots (Zubko & Day,
2002). Note that inhibition of plastid translation by high
temperatures does not lead to heritable effects (Feierabend
& Berberich, 1991), emphasizing that the origin of the
inhibitory factor is significant.
(6) Positive feedback through protein
phosphorylation
In eukaryotes, multiple examples of non-chromosomal inher-
itance have been traditionally associated with mitochondrial,
plastid, or plasmid genes (Gunge et al., 1981; Gillham,
1994; Reboud & Zeyl, 1994). However, in the 1990s some
non-chromosomal hereditary factors were shown to be pri-
ons (the term prion means ‘infectious protein’; see Prusiner,
1998; Wickner et al., 2000). Most prions discovered to date
are amyloids, and arise due to stable changes in protein
folding (see Section IV.8), but other mechanisms of hered-
itary prionization also exist. One such is positive feedback
through protein phosphorylation by the mitogen-activated
protein kinase (MAPK) cascade. This mechanism of SAEI
was described in the filamentous fungus P. anserina.
The MAPK-cascade is a regulatory phosphorylation
system intrinsic to all eukaryotes. It comprises three
sequentially functioning protein kinases: MAPKKK,
MAPKK and MAPK, where MAPK is a target for
MAPKK which is in turn phosphorylated by MAPKKK
(see Garrington & Johnson, 1999). In P. anserina, three
autonomous MAPK pathways are known: PaMpk1, PaMpk2
and PaMpk3 (Lalucque et al., 2012). Activation of the
PaMpk1 pathway causes the crippled growth phenotype (flat,
female-sterile, poorly growing, pigmented mycelium), which
is infectious to normal recipients through local anastomoses.
The molecular basis of this phenotype was designated as the
C prion (Silar et al., 1999).
Normally, PaMpk1 is activated in the stationary phase;
the corresponding variant of C is infectious but not heritable
(it ceases after the fungus returns to the growth phase).
However, if this pathway is triggered during the growth
phase, it induces a stable self-activation loop (the ON
molecules activate the OFF ones), which is infectious and
mitotically heritable (Kicka et al., 2006). In sexual crosses,
both variants of C are not transmittable (Silar et al., 1999).
Which element of the PaMpk1 pathway corresponds
exactly to C is unclear. C requires all three genes involved
in this pathway (PaASK1, PaMKK1, and PaMpk1), and can
be induced by overexpression of any of them (Kicka & Silar,
2004;Kicka et al., 2006 ; Lalucque et al., 2012). Thus, C is
likely to be conditioned by the state of the entire PaMpk1
pathway (Lalucque et al., 2012).
The heritable variant of C requires not only these three
genes (PaASK1, PaMKK1, and PaMpk1), but also increased
translational accuracy and certain genes encoding nicoti-
namide adenine dinucleotide phosphate (NADPH) oxidases
(Kicka et al., 2006; Lalucque et al., 2012). Moreover, various
stresses, including heat, ultraviolet light, high concentrations
of sucrose, and some antibiotics, lead to C curing (Silar et al.,
1999). Clearly, the appearance and deletion of this EA are
under complex genetic, developmental and environmental
control, the details of which are still obscure.
(7) Positive feedback through protein truncation
In budding yeast, more than a dozen different hereditary
prions are known (see Crow & Li, 2011; Liebman &
Chernoff, 2012). One of them, [β+
], is a self-activating form
of yeast protease B (Roberts & Wickner, 2003). This enzyme
is encoded by the PRB1 gene: the initially synthesized cat-
alytically inactive zymogene undergoes multistep maturation
(Moehle et al., 1987) and eventually is truncated by protease
A (PrA) and by protease B (PrB) itself (Nebes & Jones, 1991).
Mature PrB molecules truncate the immature ones, with
the effectiveness of this self-activation loop depending on cer-
tain genetic and environmental factors. On YPAD medium,
this loop requires PrA: deletion of PEP4 (the gene coding for
PrA) leads to the decline and eventual loss of PrB activity over
about 20 mitotic divisions (Jones, Zubenko, & Parker, 1982).
On YPG medium, PrA is not required: the cells imple-
ment PrB self-activation even if PEP4 is deleted (Roberts
& Wickner, 2003). Such cells, when transferred to YPAD,
eventually lose their PrB activity and usually cannot restore it
after returning to YPG, although restoration is possible when
PRB1 is overexpressed. Thus, under normal PRB1 expression
and in the absence of PEP4, two stable EAs can be obtained
on YPG medium: [β+
] (PrB positive) and [β−
] (PrB nega-
tive). [β+
] manifests as a dominant cytoplasmic factor heri-
table both mitotically and meiotically, and also transmittable
by cytoduction. So far, it is the only known EHF which
perpetuates through changes in protein primary structure.

Table 2. Amyloid hereditary prions
Species Prion Prion proteina
Phenotypic effectb
Reference
Saccharomyces cerevisiae [URE3]c
Ure2 Alteration of nitrogen metabolism Wickner (1994)
[PSI+
]c
Sup35 Nonsense-suppression Derkatch et al. (1996)
[PIN +
]c
Rnq1 de novo induction of [PSI+
] Derkatch et al. (2001)
[SWI+
] Swi1 Alteration of carbon metabolism Du et al. (2008)
[MOD+
] Mot3 Cell survival and drug resistance under
environmental stress
Alberti et al. (2009)
Podospora anserina [Het-s] Het-s Heterokaryon incompatibility in fusions
with the Het-S mycelium
Coustou et al. (1997)
aUre2, nitrogen catabolite repression transcriptional regulator; Sup35, a eukaryotic translation release factor; Rnq1, protein rich in
asparagine (N) and glutamine (Q); Swi1, subunit of the chromatin remodelling complex; Mot3, a transcriptional activator/modifier of
transcription; Het-s, protein encoded by the heterokaryon incompatibility locus.
b
Each of the listed prions behaves as a dominant cytoplasmic hereditary factor transmittable mitotically, meiotically and through cytoduction.
c
Clear allelic variants of the [PRION +
] state have been described.
(8) Switch of protein conformation from native
to amyloid
Amyloids are highly stable non-covalent protein aggregates
that possess a set of specific structural features [for reviews see
Baxa, 2008 and Upadhyay & Mishra, 2018]. Such aggregates
are produced from abnormally folded protein molecules,
and are able to self-perpetuate by the following mechanism
(Prusiner, 1998; Wickner et al., 2000; Liebman & Chernoff,
2012). When an amyloid interacts with native monomeric
molecules of the corresponding protein, it functions as
a conformational template: the native molecules acquire
the same amyloid folding, and are incorporated into the
aggregate. As a result, the amyloid becomes longer. Some
amyloids are then cleaved into fragments, and each fragment
can serve as an infectious ‘seed’ of the new amyloid.
Currently, amyloids are known from animals and some
fungi. In animals, they are formed exclusively in somatic cells,
and thus display infectivity but not heritability (see Prusiner,
1998). In budding yeast and P. anserina, amyloid prions
are not only infectious, but also heritable both mitotically
and meiotically as dominant non-Mendelian factors
(Table 2).
In budding yeast, at least five different amyloid prions have
been described: [URE3] (Wickner, 1994), [PSI+] (Derkatch
et al., 1996), [PIN +
] (Derkatch et al., 2001), [SWI+
] (Du
et al., 2008), and [MOD+
] (Suzuki, Shimazu, & Tanaka,
2012). In P. anserina, a single amyloid prion, [Het-s], is
known (Coustou et al., 1997). The corresponding proteins are
non-homologous and exhibit distinct physical characteristics
of their amyloid domains: the N/Q content in these domains
varies significantly (see Crow & Li, 2011; Liebman &
Chernoff, 2012).
For each of these listed amyloid prions, the [PRION +
] and
[prion−
] states represent two stable EAs with clear phenotypic
differences. Moreover, at least in three cases ([PSI+
], [PIN +
],
and [URE3]), phenotypically different allelic variants of the
[PRION +
] state are also known (see Derkatch et al., 1996;
Zhou, Derkatch, & Liebman, 2001; Schlumpberger, Pruisner
& Herskowits, 2001; Bradley et al., 2002; Brachmann,
Toombs, & Ross, 2006; Bateman & Wickner, 2013).
The best-studied hereditary amyloid prion is [PSI+
], an
aggregated isoform of the yeast Sup35 protein (Derkatch
et al., 1996). The native, soluble isoform of this protein is
involved in cytoplasmic translational termination (Stansfield
et al., 1995; Zhouravleva et al., 1995). Under rare stochastic
events strongly induced by SUP35 overexpression, the
native Sup35p molecules switch to an abnormal stable
conformation and produce the [PSI+
] amyloid (Derkatch
et al., 1996). This aggregate incorporates newly converted
Sup35p molecules, and is then fragmented by Hsp104, thus
producing the next generation of prion particles (Chernoff
et al., 1995). [PSI+
] decreases the level of translation termina-
tion and manifests as a dominant non-Mendelian nonsense
suppressor (Cox, 1965). Multiple [PSI+
] alleles distinct in
features such as mitotic and meiotic stability, suppressor
efficiency, the number of amyloid aggregates per cell, and
the proportion of aggregated Sup35p, have been described;
different [psi−
] alleles are also known (see Derkatch et al.,
1996; Zhou et al., 1999; King, 2001; Bradley et al., 2002;
Tanaka et al., 2004; Bateman & Wickner, 2013). Interest-
ingly, even from the same native Sup35p isoform, different
[PSI+
] alleles can be produced (see Liebman & Chernoff,
2012). The appearance, inheritance and elimination of
various [PSI+
] alleles depend on multiple environmental
and genetic factors (Derkatch & Liebman, 2007; Tuite &
Cox, 2007; Shorter, 2010; Liebman & Chernoff, 2012).
(9) Reproducible non-homologous protein
interaction
One non-amyloid hereditary prion identified in bud-
ding yeast, [GAR+
], is a complex produced by two
non-homologous proteins: Pma1, an essential P-type
ATPase, and Std1, a member of a molecular complex
involved in gene regulation by glucose (Brown & Lindquist,
2009). In [gar−
] cells, Pma1 is mostly associated with
the Std1 paralog Mth1, a negative regulator of the
glucose-sensing signal transduction pathway. The shift to
interaction between Pma1 and Std1 results in the production
and self-perpetuation of [GAR+
], but the exact mechanisms
involved remain obscure.

[GAR+
] cells display modified glucose repression: they
can use glycerol in the presence of glucosamine, a
non-metabolizable analog of glucose (Brown & Lindquist,
2009; Jarosz et al., 2014). This prion shows stable inheritance
both mitotically and meiotically, and is also transmittable
via cytoduction. Thus, the [GAR+
] and the [gar−
] states
represent two phenotypically distinct cytoplasmic EAs. The
appearance of [GAR+
] can be strongly enhanced by either
STD1 or PMA1 overexpression, whilst overexpression of
MTH1 results in the opposite effect. Transient absence of the
Ssa1 and Ssa2 (stress-seventy subfamily A and stress-seventy
subfamily B) chaperones leads to reversible curing of [GAR+
].
Interestingly, this prion is totally cured in response to deletion
of both STD1 and the N-terminus of PMA1, but successfully
propagates in the presence of only one of these listed deletions
(Brown & Lindquist, 2009). We have no explanation for this
intriguing observation.
(10) Reproducible differences in cortex structure
The cortex of a Paramecium cell contains thousands of ciliary
basal bodies aligned in multiple longitudinal rows. Each
basal body connects to a ciliary rootlet, which usually
runs anteriorly (ciliate cells display clear dorso-ventral and
antero-posterior polarity) and slightly to the right (Iftode et al.,
1989). Normally, all rootlets have a similar orientation, thus
providing well-coordinated cell movement; however, some
Paramecium cells display so-called ‘twisty’ swimming due to
the presence of one or several inverted ciliary rows.
During division, the cell undergoes duplication of its
basal bodies, with new rootlets keeping the same polarity
as ‘maternal’ ones; thus, the structure of the cortex is clonally
inherited (see Beisson, 2008). This cortical inheritance was
experimentally verified by grafting small pieces of cortex
in the reverse orientation (Beisson & Sonneborn, 1965).
Following a successful graft, the inverted row segment
elongates progressively over several cell divisions leading
to complete inverted row establishment, and the altered
phenotype is then reproduced in all mitotic generations.
Moreover, since sexual process in ciliates is usually
accomplished through conjugation without cell fusion, this
phenotype is maternally inherited in sexual crosses (Beisson
& Sonneborn, 1965).
Another example of cortical inheritance in Paramecium
is the reproduction of complete doublets, the results of
occasional abnormal conjugation where two mates fuse
in a tandem cell possessing a double set of all organoids
(Sonneborn, 1963). Similarly to inverted ciliary rows, the
doublet phenotype is perpetuated in mitotic divisions, and
displays maternal inheritance in sexual crosses (doublets can
be crossed with normal cells). Thus, these different variants
of cortex structure are allelic non-Mendelian EHFs.
Cortical inheritance is described not only in Paramecium,
but also in some other ciliates: Tetrahymena, Oxytricha
and Paraurostyla (Ng & Frankel, 1977; Hammersmith &
Grimes, 1981; Fleury et al., 1993), although the details may
vary significantly. In Oxytricha and Paraurostyla, the ciliary
apparatus undergoes complete de-differentiation during each
division or encystment, and is subsequently differentiated de
novo. Nevertheless, the newly developed ciliary apparatus
corresponds exactly to the ‘maternal’ one. The mechanism
by which this structural memory is achieved is unknown, but
it thought to relate to a centrin-containing scaffold associated
with ciliary basal bodies (Ruiz et al., 2005).
(11) Other possible mechanisms
In addition to the above mechanisms of SAEI, two
hypothetical mechanisms are here proposed.
In plants and lower eukaryotes, organellar introns display
ribozyme activity: they catalyse their own excision from RNA
due to a highly conservative secondary structure (see Haugen,
Simon, & Bhattacharya, 2005; Zimmerly & Semper,
2015). Some introns are self-spliced, but others require
stabilization of their secondary structure by specific proteins
called maturases (Vicens et al., 2008). Fig. 2 illustrates a
hypothetic digenic system, where SAEI could result from
maturase-facilitated splicing. One gene serves as a marker. It
is interrupted with an intron, whose secondary structure
is quasi-appropriate and determines very low-efficiency
self-splicing. Another gene encodes the required maturase,
and contains a copy of the same intron. Typically, both
introns are not excised, leading to stable heritability of
the mutant phenotype (the OFF state). Rare occasional
self-splicing of the marker gene intron is insufficient for
a normal phenotype, and causes only a slightly ‘leaky’
effect. But when the maturase gene intron is occasionally
self-spliced, even from a single transcript, ‘illegitimate’
maturase is produced. Under these conditions, splicing of the
maturase gene intron can perpetuate due to positive feedback
as a dominant cytoplasmic factor and will show stable
inheritance both mitotically and meiotically (in each type
of division, the newly produced maturase will be transmitted
with a portion of the cytoplasm to each daughter cell). The
marker gene intron will also be excised; thus allowing a
normal phenotype (the ON state) with stable inheritance to
be established. These two alternative states of this proposed
system could manifest as clear non-Mendelian EAs.
Anotherpossible mechanism concerns post-transcriptional
silencing through RNA interference. As was noted above,
involvement of small RNAs in SAEI is well documented, but
they usually function in guiding histone modifications and/or
DNA methylation/demethylation (for a review, see Allis et al.,
2007; Hollick, 2016; Lebedeva et al., 2017). To date, there are
no clear examples of SAEI provided by small RNA-mediated
post-transcriptional silencing without stable changes at the
transcription level. However, recent studies in Paramecium
tetraurelia are quite promising. This unicellular organism has
a very unconventional sexual process: two cells of opposite
mating types (E and O) conjugate and exchange their genetic
material such that the genotype of both cells becomes
identical (see Sonneborn, 1974). Moreover, although the mtA
gene, the key mating-type-controlling gene in Paramecium,
is chromosomal, each participant retains its initial mating
type, so the trait is inherited maternally. This phenomenon

Fig. 2. A hypothetical mechanism of stable allelic epigenetic inheritance (SAEI) provided by a self-sustaining loop through
maturase-facilitated splicing. The exonic and intronic regions of genes/transcripts are marked in black and grey, respectively. In
transcripts, the intronic regions are schematically shown as single spindles. (A) OFF state. Both introns fail to acquire an appropriate
secondary structure due to maturase absence and thus are not excised and neither the maturase nor the marker protein is synthesized.
(B) ON state. In the presence of the maturase, the secondary structure of both introns is appropriately stabilized, and each is
self-spliced. As a result, the marker protein and the maturase are synthesized, and the latter provides stable positive feedback.
is controlled by special scanning RNAs (scnRNAs), which
regulate the fate of the mtA gene in the macronucleus (Singh
et al., 2014). A Paramecium cell has two different types of
nuclei in its cytoplasm. One of these, the micronucleus (Mic),
represents the germline; its genome contains thousands of
transposons and internal eliminated sequences, and is silent.
The second, the macronucleus (Mac), is produced from a
mitotic copy of the Mic, and functions as the soma; during
its development, all transposons and internal eliminated
sequences are removed by deletions, the remaining DNA
is polyploidized and is used for phenotype formation. At
the same time, certain genes can undergo targeted loss of
their promoters and become silent. During conjugation, the
maternal Mac degenerates, but its transcripts remain in the
cytoplasm temporarily, and are scanned by the scnRNAs
transiently synthesized in the maternal Mic. The aim of this
scanning is to check the state of the maternal Mac genome,
and to reproduce it in the new Mac. In particular, expression
of the mtA gene in the maternal Mac (this leads to the E
mating type) causes interference between the transcripts and

the mtA-specific scnRNAs. As a result, the scnRNAs are
digested, and thus are unable to affect the mtA promoter
in the new Mac; therefore, the daughter cell inherits the
maternal E mating type. But if there is no such interference
(i.e. the mtA gene was silent in the maternal Mac, and thus the
cell displayed the O mating type), the mtA-specific scnRNAs
are not digested, and guide deletion of the mtA promoter in
the new Mac. Thus, the daughter cell inherits the maternal
O mating type (Singh et al., 2014).
In this exotic mechanism, the absence of RNA interference
guides promoter deletion. The resulting inheritance is not
entirely epigenetic. However, a modified scanning scheme
is theoretically possible. Here, the gene is also expressed in
Mac, but its regulation will depend on the presence/absence
of the encoded protein (Fig. 3). The protein is rather stable: it
persists in the cytoplasm after conjugation or cell division and
thus serves as a marker of the maternal state. The scnRNAs
are intensively produced in the Mic during all stages of the
cell cycle, and are able to interact with both the protein
and the gene transcripts. Interaction with the protein leads
to rapid digestion of the scnRNAs. Thus, if the protein is
synthesized in the maternal cell (the ON state), the scnRNAs
are digested and do not affect expression of the new Mac
genome. But if the protein is not synthesized in the maternal
cell (the OFF state), the scnRNAs remain intact and interfere
with the gene transcripts, providing post-transcriptional gene
silencing. Theoretically, therefore the ON and OFF states
of this system should be two stable EAs produced through
scanning-dependent RNA interference.
V. WHAT DO MECHANISMS OF SAEI HAVE IN
COMMON? THE BIMODULARITY PRINCIPLE
In the first descriptions of the mechanisms involved in SAEI
(DNA methylation/demethylation, histone modification,
and amyloid prionization), a template principle of EA
reproduction was posited (see Jablonka & Raz, 2009).
Since this principle also underlies DNA-sequence-mediated
inheritance, it is considered by some geneticists to represent
a universal concept of inheritance, both canonical and
epigenetic (Inge-Vechtomov, 2013, 2015). However, there
are two crucial problems. First, depending on the particular
mechanism of SAEI involved, epigenetic templates may
be highly distinct. For DNA methylation/demethylation,
the templates are linear, and their reproduction is
semi-conservative (Vanyushin & Ashapkin, 2011). Histone
modification patterns outwardly resemble a linear template,
but the epigenetic marks are distributed between multiple
non-covalent components of the same chromosome, and the
mode of reproduction (conservative or semi-conservative,
replication or reconstruction) is still unclear (Cheedipudi
et al., 2014). Amyloid prions are also templates, but not linear;
in this case, conformational templating occurs. Reproduction
of amyloid prions is semi-conservative: a prion aggregate
is cleaved into fragments, with each of them becoming
the ‘seed’ of a new template (Liebman & Chernoff, 2012).
Templates are typical for cortical inheritance as well, but they
are spatial (i.e. they carry information about the position and
Fig. 3. A hypothetical mechanism of stable allelic epigenetic inheritance (SAEI) provided by a self-sustaining loop through scanning
RNA (scnRNA) interference. Ma, macronucleus; Mi, micronucleus; star shapes represent the gene-encoded protein (GEP). (A) OFF
state: GEP is absent. The scnRNAs are not digested and cause gene silencing via RNA interference. (B) ON state: GEP is present
(open symbols). The scnRNAs are rapidly digested by the GEP and thus fail to interfere with the gene transcripts. Therefore, the
gene is not silenced, and the newly synthesized molecules of GEP (filled symbols) provide stable positive feedback.

Table 3. Molecular differences between distinct alleles of the yeast amyloid prion [PSI+
]
DNA determinant Epigenetic determinant Prion allelea Features of the prion allele
SUP35ref
reference SUP35 sequenceb
[PSI+
]S
‘weak’ prionized Sup35p
SUP35ref
[PSI+
]S
[PSI+
]; reference Sup35p sequence; strong
suppressor efficiency
SUP35ref [PSI+]W
‘strong’ prionized Sup35p
SUP35ref [PSI+]W [PSI+]; reference Sup35p sequence; weak
suppressor efficiency
SUP35ref
[psi−
]
native Sup35p
SUP35ref
[psi−
] [psi−
]; can be epigenetically converted to
SUP35ref
[PSI+
] by most of the known [PSI+
]
alleles
SUP35PNM2
PNM2 mutation in SUP35c
[psi−
] SUP35 PNM2
[psi−
] [psi−
]; can be epigenetically converted to
SUP35PNM2
[PSI+
] by only some specific
[PSI+
] alleles
SUP35 N
SUP35 N-region deletiond
[psi−] SUP35 N [psi−] [psi−]; cannot be epigenetically converted to
[PSI+] by any [PSI+] allele
SUP35ref
[PSI+
]ETA
SUP35ref
[PSI+
]ETA
Atypical [PSI+
]; reference Sup35p sequence; very
weak suppressor efficiency; causes lethality
when combined with the sup35–2 mutatione
SUP35PNM2
[PSI+
]VH-1
SUP35PNM2
[PSI+
]VH-1
[PSI+
]; reproducible in the SUP35PNM2
backgroundf
a
Designation of a prion allele is bimodular: (i) a DNA determinant reflecting the amino acid sequence of Sup35p, and (ii) the epigenetic
state of this protein (Tikhodeyev et al., 2017).
b
The wild-type SUP35 sequence typical of laboratory strains, including known natural polymorphism (Bateman & Wickner, 2013).
c
In the SUP35PNM2
(psi-no-more) background, [PSI+
] of the reference Sup35p sequence fails to reproduce and is lost (Doel et al., 1994).
d
The SUP35 gene is essential and thus cannot be deleted (Ter-Avanesyan et al., 1993). However, it is possible to delete its N-region, which
is required for Sup35p prionization, but does not affect viability (Ter-Avanesyan et al., 1994). In the SUP35 N
background, no [PSI+
] can
be reproduced.
eZhou et al. (1999).
f King (2001).
orientation of cell organoids), and duplication of cortical
elements is conservative (Beisson, 2008).
Second, in several mechanisms of SAEI, reproduction
of EAs is accomplished through a positive feedback loop
without evident templates. This is characteristic of bistable
transcriptional networks (Gardner et al., 2000; Tchuraev
et al., 2000; Gordon et al., 2009), inhibition of plastid
translation (Zubko & Day, 1998, 2002), all non-amyloid
prions (Roberts & Wickner, 2003; Kicka et al., 2006; Brown
& Lindquist, 2009), and both hypothetical mechanisms
proposed above (Section IV.11). Moreover, any other
self-sustaining loop, irrespective of its mechanism, could
provide the basis for epigenetic inheritance (Jablonka &
Lamb, 2005; Jablonka & Raz, 2009). Thus, the template
principle is not universal.
Nevertheless, all mechanisms of SAEI display a fun-
damental similarity. Each EA is a bimodular unit, the
features of which depend on two principal determinants
(Tikhodeyev et al., 2017): a DNA determinant (DNA
sequence) and an epigenetic determinant (epigenetic mark
on the DNA sequence or its product). The best model
to illustrate this bimodularity is the yeast amyloid prion
[PSI+] which has hundreds of known allelic variants. To
perpetuate a particular [PSI+
] allele the cell must possess
both: (i) a specific epigenetic mark as a ‘seed’, and (ii) the
corresponding SUP35 sequence, in the absence of which
the allele will not be reproduced because of the absence of
the necessary protein (see Tikhodeyev et al., 2017). Multiple
[PSI+
] and [psi−
] alleles have been described (see Table 3).
Some of these, e.g. SUP35ref
[PSI+
]S
, SUP35ref
[PSI+
]W
and SUP35ref [psi−], possess the same DNA determinant
and differ only in the epigenetic marks. By contrast,
prion alleles such as SUP35ref
[psi−
], SUP35PNM2
[psi−
] and
SUP35 N
[psi−
] are identical in their epigenetic mark (all are
ENAs) and differ only in the DNA determinant. Finally, in
the most complicated cases, both determinants are affected.
The bimodularity principle can be used to describe any
stable EA as a combination of the corresponding DNA
and epigenetic determinants. Any novel combination, if not
lethal or unstable, could result in a novel EA. Depending on
both determinants, these novel EAs can be either distinct in
their manifestation, or phenotypically similar like canonical
‘DNA-only’ alleles with silent polymorphism.
The bimodularity principle can be applied to any SAEI
mechanism known or hypothetical (Table 4). Thus, it is a
first step towards creating a general theory of SAEI to cover
all mechanisms and resulting phenomena.
In most EAs, a DNA determinant is represented by a single
gene; however, in some cases, it is polygenic (see Table 4).
By analogy, the epigenetic determinant can be either single
or multifactorial. For example, if an epiallele produced by
DNA methylation possesses multiple methylation sites, each
is per se an autonomous epigenetic mark that should be
analysed separately (see Mikeska, Candiloro, & Dobrovic,
2010). A similar approach is applicable to various chemical
modifications of the same histone (see Allis et al., 2007). Even

Table4.Bimodularnatureofepigenealleles(EAs)indifferentmechanismsofstableallelicepigeneticinheritance(SAEI)(adaptedfromTikhodeyevetal.,2017)
MechanismSpeciesDNAdeterminantEpigeneticdeterminantEAaReferences
DNAmethylation/demethylationArabidopsisthalianaBALregionofchromosome4bNormalmethylationoftheBAL
region
WildtypeKakutanietal.(1999)
HypomethylationoftheBAL
region
BALepimutationc
HistonemodificationsA.thalianaFLCregionofchromosome5bH3K27me3associatedwiththe
FLCregion
SilencedFLCBastowetal.(2004)
H3K27associatedwiththeFLC
region
Wildtypec
Positivefeedbackbytranscription
factors
Escherichiacolilacpromoter,
lacIandlacYd,e
PresenceoflacrepressorBistablelacoperonOFFCaietal.(2006)
AbsenceoflacrepressorBistablelacoperonONc
Positivefeedbackthrough
self-splicing
HypotheticalQuasi-appropriateintroninthe
maturasegenee–g
PresenceofmaturaseSelf-splicingONThisarticle
AbsenceofmaturaseSelf-splicingOFFc
Scanning-dependentRNA
interference
HypotheticalGenescodingforandregulated
byscanningRNAs
(scnRNAs)e–g
PresenceofencodedproteinGenesilencingOFFThisarticle
AbsenceofencodedproteinGenesilencingONc
Inhibitionofplastidtranslationby
antibiotics
NicotianatabacumPlastidgenesforribosomal
proteinse–g
Presenceoffunctionalplastid
ribosomes
WildtypeZubko&Day(1998)
Absenceoffunctionalplastid
ribosomes
albinophenocopyc
Positivefeedbackthroughprotein
phosphorylation
PodosporaanserinaGenesforthePaMpk1hpathwaye,fSelf-activatedstateofPaMpk1PrionCLalucqueetal.(2012)
Non-activatedstateofPaMpk1Wildtypec
Positivefeedbackthroughprotein
truncation
SaccharomycescerevisiaePRB1fSelf-activatedstateofproteaseB[β+]Roberts&Wickner(2003)
NormalstateofproteaseB[β−]c
SwitchtoamyloidconformationS.cerevisiaeSUP35f
AmyloidconformationofSup35ph
SUP35[PSI+
]Derkatchetal.(1996)
NativeconformationofSup35pSUP35[psi−
]c
Non-homologousproteininteractionS.cerevisiaePMA1,STD1e,fAssociationbetweenPma1pand
Std1pg,h
[GAR+]Brown&Lindquist(2009)
AssociationbetweenPma1pand
MTH1pg,h
[gar−
]c
Reproducibledifferencesincortex
structure
Parameciumsp.Genesencodingcortical
proteinse,f
Invertedpositionofciliarybasal
bodies
InvertedciliaryrowsBeisson(2008)
Wild-typepositionofciliarybasal
bodies
Wildtype
aAtpresent,clearbimodularnomenclatureisgivenonlyforamyloidhereditaryprions(seeTikhodeyevetal.,2017).
bTheDNAdeterminantispartofthecorrespondingEA.
c
Epigeneticnull-alleles(ENAs).
d
ThelacpromoterispartofthecorrespondingEA(itisatargetforthelacrepressor).lacIandlacYaffectthefeaturesoftheEAsviadefiningthesequencesoftheencodedproteins.
eMultigenicDNAdeterminant.
fTheDNAdeterminantaffectsthefeaturesofthecorrespondingEAsviadefiningthesequence(s)oftheencodedRNA(s)and/orprotein(s).
g
Seetextfordetails.
h
PaMpk1,mitogen-activatedproteinkinasecascade1;Sup35p,aeukaryotictranslationreleasefactor;Pma1p,anessentialP-typeATPase;Std1p,amemberofamolecularcomplexinvolvedingene
regulationbyglucose;Mth1p,anegativeregulatoroftheglucose-sensingsignaltransductionpathway.

phenotypically equal epialleles might be distinct in the precise
distribution of the methylated sites; these epialleles should
be considered as distinct as ‘DNA-only’ alleles produced by
silent polymorphism.
It should be stressed that different epigenetic marks can
interact with each other in an EA. This is well known for
DNA methylation and histone modifications (see Allis et al.,
2007). In such cases, all the corresponding epigenetic marks
should be taken into account as representing a multifactorial
epigenetic determinant. The interacting epigenetic marks
may also differ in how they are transmitted: some may
perpetuate via replication and serve as signals for the
reconstruction of others.
If the genome is represented by RNA, as in RNA-
containing retroviruses, the genomic RNA-determinant
should be used instead of the DNA determinant.
VI. ADVANTAGES OF THE BIMODULARITY
PRINCIPLE
Among the conceptualisations of EI (see Section I), the most
similar to the bimodularity principle is the concept of EISs
(Jablonka & Lamb, 1995, 2002, 2005). In both cases, a
multiplicity of EI mechanisms is postulated, and a significant
role of DNA is assumed. In other aspects these concepts differ
significantly.
First, each EIS is considered as a specific mechanism.
As a result, the concept of EISs is process-oriented: it pays
attention to the underlying processes and their interactions,
but not to each of the possible allelic states. By contrast, the
bimodularity principle describes any allelic states produced
by a particular mechanism or combination of different
mechanisms.
Second, the notion of an epiallele in the concept
of EIS differs substantially from that of an EA in
the bimodularity principle. The term ‘epialleles’ means
alternative heritable forms of a gene with an unchanged
DNA sequence distinct in DNA methylation/demethylation
or other chromatin-related marks (Jablonka & Lamb,
1995, 2005). EAs are much more variable than this
since the underlying mechanisms are not limited to
chromatin-related ones. Moreover, EAs can differ from each
other either in the epigenetic determinant, or in the DNA
determinant, or in both. For instance, SUP35ref
[PSI+
]S
and SUP35PNM2
[PSI+
]VH-1
(see Table 3) are EAs but not
epialleles since their DNA determinants are not the same.
Similar situations might arise when the mechanism of EI
is related to chromatin marking. Indeed, let us imagine
that two different DNA alleles (a1 and a2) are methylated,
producing the corresponding epialleles (a1
met1
and a2
met2
).
When compared to each other, a1
met1
and a2
met2
would
be EAs but not epialleles following the same logic. Thus,
epialleles represent a particular case of EAs.
Third, unlike the concept of EISs, the bimodularity
principle should allow us to establish a simple and useful
nomenclature for EAs. This nomenclature was proposed
previously for amyloid prion alleles (Tikhodeyev et al.,
2017; see Table 3). It successfully describes even exotic
(non-multiplied and non-reproduced) prion states, thus is
applicable not only to SAEI but also to more complicated
modes of EI. A similar nomenclature could be used for any
EAs possessing a single-gene DNA determinant and single
epigenetic determinant. In the cases when either a DNA or
an epigenetic determinant is multifactorial, upgrading of this
nomenclature will be required.
Thus, the bimodularity principle is a novel step in the
development of cellular EI concepts. It is also potentially
applicable at least to some cases of body-to-body information
transfer (see Section VII). It aggregates the best elements
from previous concepts of plasmogene, epigene, EIS, protein
inheritance, and two-level templates. Moreover, it provides
a set of important advantages allowing simple, useful, and
clear description of most known EAs.
We believe that the term ‘epigene’, although infrequently
used at present, has advantages over ‘epigenetic inheritance
system’. Epigene is shorter, and means a hereditary unit,
not a process, thus allowing a clear and useful association
between epigene (non-canonical hereditary unit) and gene
(canonical hereditary unit). Moreover, ‘epigene’ actually has
priority since it was coined far earlier (Tchuraev, 1975).
VII. PERSPECTIVES
Different steps of gene expression and various mechanisms
of gene-product functioning may be involved in SAEI. These
include (i) regulation of transcription by DNA methylation,
histone modifications, and transcription factors, (ii) RNA
splicing, (iii) small RNA-mediated post-transcriptional
silencing, (iv) stable inhibition of organellar translation,
(v) protein processing by truncation, (vi) post-translational
chemical modifications, (vii) protein folding, and
(viii) homologous and non-homologous protein interactions.
The breadth of the above list suggests that there are no
specific mechanisms of SAEI. Any or almost any regulatory
mechanism participating in gene expression or gene-product
functioning, under certain circumstances, may underlie the
production of allelic differences with stable inheritance.
Novel mechanisms of SAEI are likely to be described in
the near future.
At first glance, the absence of a strict correlation
between molecular mechanisms and heredity is astonishing,
prompting us to consider whether a general theory of
inheritance or a general theory of SAEI can ever be
formulated. However, the most fundamental laws in physics
are principal taboos: it is impossible to create a perpetuum
mobile, or to measure precisely both the speed and coordinates
of an electron, etc. Similar situations arise in modern biology
(see Sverdlov, 2009). So, it is possibly not strange that the
theory of inheritance acquires its own principal taboo: it
is impossible at present to find a clear correlation between
molecular mechanisms and their hereditary effects, reflecting

that the complexity of life is significantly greater than
encompassed by the DNA theory.
The idea that all hereditary factors are ‘DNA-only’ is
obviously outdated. However, a role of DNA cannot be
ruled out, even by so-called ‘protein inheritance’. Indeed,
each known EA possesses a DNA determinant; so the role of
DNA is still fundamental although as an element of a more
complicated concept. In accordance, any stable hereditary
factor depends on a DNA determinant, but at least in some
cases an epigenetic determinant is also present, and there are
no (or almost no) limitations on the underlying mechanisms.
As noted above, the broad sense of EI covers not only
cellular EI but also body-to-body information transfer via
mother–embryo developmental interactions, social learning,
and symbolic communications (Jablonka & Lamb, 2005,
2006). At present, the bimodularity principle relates
exclusively to cellular EI because the mechanisms of
body-to-body information transfer are unknown. However, if
these mechanisms were explored and involve allelic variants
of the transferred information, such cases might also be
described by the bimodularity principle. In this regard, one
of the most promising phenomena is imprinting of courtship
song in zebra finches (Taenopygia guttata): a young male chick
remembers a male courtship song heard during a specific
period of development, and reproduces it when becomes
an adult (see Adret, 1993). As a result, the male song is
transmitted to further generations, either from fathers to
sons or from adult males to unrelated young males. This is a
typical example of epigenetic inheritance via reconstruction
of a regulatory state, and the reconstruction machinery
is likely to be complex and multifactorial with different
interacting mechanisms.
In zebra finches, multiple variants of the male courtship
song exist, among which alternative elements can be
discerned (Eales, 1985; Clayton, 1987). Such elements are
per se allelic. Notably, if the chick is too young or too
old, imprinting does not occur (Adret, 1993); so, the same
‘courtship song allele’ can be either transmittable to a
particular chick or not. This situation strongly resembles
the general rule of EI in that heritability of an EA depends
on specific conditions (see Sections II, IV).
Although the mechanisms of courtship song imprinting
are still unknown, they will involve regulatory processes in
the neural structures of the brain in response to specific
external stimuli (see Tikhodeyev, 2016). These processes
are likely to depend on the chick’s genotype. Therefore,
a certain ‘courtship song allele’ might hypothetically be
described as a combination of (i) a highly polygenic DNA
determinant including all genes involved in the imprinting,
and (ii) an epigenetic determinant represented by molecular
effects triggered within the chick brain by hearing the
song. ‘Courtship song null-alleles’ are also possible; such
alleles should arise if the chick did not hear any courtship
song, or if the developmental period was inappropriate
for imprinting. Thus, the bimodularity principle might be
useful even for some cases of body-to-body information
transfer.
VIII. CONCLUSIONS
(1) There are no specific mechanisms of stable allelic
epigenetic inheritance. Any or almost any regulatory
mechanism involved in gene or gene-product function-
ing (e.g. regulation of transcription by DNA methylation/
demethylation, histone modifications, and transcription
factors; RNA splicing; RNA-mediated post-transcriptional
silencing; organellar translation; protein processing by trun-
cation; post-translational chemical modifications; protein
folding; homologous and non-homologous protein inter-
actions) may occur under appropriate conditions.
(2) Any stable epigenetic hereditary factor can be seen as
a bimodular unit comprising (i) a DNA determinant, and
(ii) an epigenetic determinant. Some epigenetic hereditary
factors are allelic, i.e. they represent various states of the
same epigene, a hereditary unit, in which some part of
information is kept, reproduced, and transmitted to the
progeny beyond the primary structure of DNA. Various
alleles of the same epigene can differ from each other either
in the DNA determinant, or the epigenetic determinant, or
both. In cases when the genome is represented by RNA, the
genomic RNA determinant is involved, rather than the DNA
determinant.
(3) Any new combination of these two determinants (if
stable and non-lethal) leads to establishment of a novel allele
of an epigene.
(4) The genetic role of DNA is fundamental to all
stable hereditary factors. However, some hereditary factors
are ‘DNA-only’, while others are bimodular and involve
epigenes.
(5) The bimodularity principle should allow us to establish
a simple and useful nomenclature for any epigene alleles
possessing a single-gene DNA determinant and a single
epigenetic determinant. In cases when either a DNA or an
epigenetic determinant is multifactorial, upgrading of this
nomenclature will be required.
(6) The bimodularity principle successfully includes not
only stable allelic epigenetic inheritance but at least some
more complicated modes of inheritance like progressive
weakening of a heritable trait over generations. Moreover, it
is potentially applicable even to some cases of body-to-body
information transfer.
(7) The bimodularity principle should help us to develop
modern concepts of inheritance that cover both canonical
and ‘non-canonical’ hereditary phenomena.
IX. ACKNOWLEDGMENTS
The author is grateful to Stanislav A. Bondarev and Oleg
V. Tarasov for extensive discussions on the bimodularity
principle, and to anonymous referees for very useful advice.
The author would also like to thank Vyacheslav N. Bolshakov
and Alison Cooper for kind help in preparation of the text,
and Nickolay O. Tikhodeyev for preparation of the figures.

This work was supported by a grant from The Russian
Foundation for Basic Research, no. 15-04-05579.
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