This slide covers basics of epigenetics and epigenetic effects and the influence of epigenetics on cancer

2. CONTENTS
 Introduction
 Chromatin
 Histone
 Histone modifications
 DNA methylation
 Epigenetic effects
 Epigenetics and cancer
 Scope
 Conclusion

3. INTRODUCTION
 Epigenetics is heritable modifications to DNA that alter
gene expression but not nucleotide sequence of genome
 Retained through cell divison and passed on to future
generations and influenced by environmental factors
 After replication,epigenetic mark remains on template
strand which recruit enzymes that make similar changes
in new strand
 Some of the epigenetic “tags” remain in place and
therefore pass from generation to generation, this is
called epigenetic inheritance

4.  Paul Kammerer, a lamarckian
evolutionist, in the 1920s
considered the discoverer of
non-Mendelian epigenetic
inheritance
 C.H. Waddington coined the
term epigenetics in 1942

5. CHROMATIN
 Complex of DNA with an equal weight of basic proteins
called histones
 Histone protein forms octamer around which helical DNA
coils tightly
 Euchromatin-Transcriptionally active, less compact
Heterochromatin-Less transcriptionally active, very
compact

7. HISTONES
 Basic protein and positively charged
 Five types-H1,H2A,H2B,H3,H4
 H1 acts as a bridge between adjacent
nucleosome
 Octamer has two domains
-globular which interacts with DNA and histones
-positively charged tail which interacts with
phosphate groups of DNA
 Tails of histones can undergo a variety of
posttranslational covalent modifications including
methylation, acetylation on specific residues

10. HISTONE MODIFICATION
 Methylation
– Addition of methyl to tail;activation/repression
depending upon which amino acid in tail is
methylated.
– Methylation can either prevent certain proteins
from binding to DNA, or it can attract certain
proteins with repressing properties.
– Histone methylases are known to specifically
methylate H3 at lysine 4 and lysine 9.

11. – Methylation at H3 lysine 4 characterizes active genes –
facilitates transcription in part by protecting active
coding regions from deacetylation and by promoting
recruitment of transcriptional complexes
– Methylation of H3 lysine 9 characterizes inactive genes –
it leads to recruitment of HP1(heterochromatin protein)
which induce heterochromatin formation

12.  Acetylation-
– Stimulates transcription because chromatin is in open
configuration and available for transcription
– Added by Histone acetyl transferase (HAT) enzyme
– Weakens interaction of tail with DNA and permits
transcription factors to bind to DNA

14. DNA METHYLATION
 Covalent addition of methyl group to 5th Position of
cystosine with in CPG di-nucleotides which are
frequently located in the promoter region of genes.
 Complex process catalyzed by DNA methyl transferase.
 Attracts deacetylase which removes acetyl group from
histone tails and stabilizes nucleosome structure thus
represses transcription

15.  Lead to gene silencing by either preventing or
promoting the recruitment of regulatory proteins to
DNA
 Most seen in female mammals where the inactive X-
chromosome is extensively methylated
 Also seen in regions containing repetitive sequences
including those that are rich in transposable
elements

17. EPIGENETIC EFFECTS
 Monozygotic Twins
‒ Identical twins are from the same zygote, so they begin
life with the same genetic information, including
epigenetic tags
‒ The phenotypic difference in the twins epigenomes is
what makes them become different when they are older
‒ The epigenetic tags can have such an effect on the twins
that one can develop a disease while the other is fine

18. ‒ Differences prevelant in
older twins
‒ Due to fluctuations in
transmission of histone
modifications and DNA
methylation

19. Epigenetic imprinting
‒ Suppression of
certain genes on chromosomes,
depending on from which parent
they were received
– The expression of a gene that is
imprinted is conditioned by
parental origin
– Ensure transposable elements
remain epigenetically silenced
throughout gametogenic
reprogramming to maintain
genome integrity

20. – The alleles of imprinted genes are marked epigenetically
at imprinting control regions (ICRs) with their parental
origin in gametes through the use of DNA methylation
– There are currently more than 50 known imprinted human
genes,play a part in morphogenesis,cell growth
– In mice,the Igf2 gene is expressed when it is inherited
from father and not from mother

22.  Prader-willi syndrome-the paternal chromosome 15 is
imprinted
 Angelman syndrome-the maternal chromosome 15 is
imprinted

23. EPIGENETICS AND CANCER
 Aberrant DNA methylation patterns associated with a
large number of human malignancies and found in two
distinct forms
-hypermethylation causes cancer by silencing the
expression of tumor suppressor gene
-hypomethylation activates oncogenes
 Cancer epigenome is marked by genome-wide
hypomethylation and site-specific CpG island promoter
hypermethylation
 DNA hypomethylation at repeat sequences leads to
increased genomic instability by promoting chromosomal
rearrangements

24.  p16, a gene that normally functions to prevent cancer
but is commonly methylated in a broad spectrum of
human cancers.
 An approach to engineer DNA methylation specifically
to the mouse p16 regulatory region (promoter) has
been devised.
 The engineered p16 promoter acts as a 'methylation
magnet'. As the mice reaches adulthood, gradually
increasing p16 methylation leads to a higher incidence
of spontaneous cancers.
Yu et al., Journal of Clinical Investigation, 2014

25. Robertson, Nature Reviews Genetics, 2005
Figure: DNA methylation and cancer

26. SCOPE OF EPIGENETICS
 Epigenetic pharmaceuticals could be a replacement for
currently accepted treatment methods such as
radiation and chemotherapy, or could enhance the
effects of these current treatments. Epigenetics also
has the factor of reversibility, a characteristic that other
cancer treatments do not offer
 Vornistat is an HDAC inhibitor.HDAC has been shown to
play an integral role in the progression of oral
squamous cancer

27.  Azacitidine,an epigenetic drug is used to treat a blood
disease called myelodysplastic syndrome
 The Roadmap Epigenomics Program,a$190 million
project started in 2008 by the National Institutes of
Health

28. CONCLUSION
 Epigenetics refers to heritable changes in gene
expression that does not involve changes to the
underlying DNA sequence
 Two prominent epigentic mechanisms involve DNA
methylation (gene silencing) and histone acetylation
(gene activation) and methylation
 Errors in epigenetic patterns can influence the
presentation of human diseases including cancer
 New and ongoing research is continuously uncovering
the role of epigenetics in a variety of human disorders
and fatal diseases.
 Drugs that influence the epigenome represent a major
area of current research