-Basic Concepts in Genetics -What is Epigenetic? -History of Epigenetic -How do epigenetics work? -Epigenetics and the Environment -Epigenetic Inheritance -Epigenetics in Psychiatry

1. EPIGENETICS

2. Agenda
• Basic Concepts in Genetics
• What is Epigenetic?
• History of Epigenetic
• How do epigenetics work?
• Epigenetics and the Environment
• Epigenetic Inheritance
• Epigenetics in Psychiatry

3. Basic
Concepts in
Genetics

4. Cells are fundamental working units
of every human being. All the
instructions required to direct their
activities are contained within the
chemical deoxyribonucleic acid,
also known as DNA.

5. DNA from humans is made up of
approximately 3 billion nucleotide bases.
There are four fundamental types
of bases that comprise DNA – adenine,
cytosine, guanine, and thymine, commonly
abbreviated as A, C, G, and T,
respectively.

6. The sequence, or the order, of the bases is
what determines our life
instructions. Interestingly enough, our
DNA sequence is more than 99 percent
similar to that of a chimpanzee. Less than
1 percent, or 15 million bases, has a
distinctively different sequence that makes
us human.

7. Within the 3 billion bases, there are about
20,000+ genes. Genes are specific
sequences of bases that provide
instructions on how to make
important proteins –that trigger various
biological actions to carry out life functions.

8. A genome is an organism’s complete set of DNA,
including all of its genes. Each genome contains
all of the information needed to build and
maintain that organism. In humans, a copy of the
entire genome—more than 3 billion DNA base
pairs—is contained in all cells that have a
nucleus.

9. What Are Epigenetics?

10. Epigenetics literally means "above" or "on
top of" genetics. It refers to external
modifications to DNA that turn genes "on"
or "off." These modifications do not change
the DNA sequence, but instead, they affect
how cells "read" genes.

11. The term epigenetics refers to heritable
changes in gene expression (active versus
inactive genes) that does not involve
changes to the underlying DNA sequence;
i.e. a change in phenotype without a
change in genotype.
(Cold Spring Harbor meeting in 2008)

12. Epigenetic change is a regular and natural
occurrence but can also be influenced by
several factors including age, the
environment/lifestyle, and disease state.
Epigenetic modifications can manifest as
commonly as the manner in which cells
terminally differentiate to end up as skin
cells, liver cells, brain cells, etc.

13. Epigenetic change can have more damaging
effects that can result in diseases like cancer. At
least three systems including
– DNA methylation,
– histone modification and
– non-coding RNA (ncRNA)-associated gene
silencing are currently considered to initiate and
sustain epigenetic change.

14. History of
Epigenetics

15. • The term epigenetics, which
was coined by Conrad H.
Waddington in 1942, was
derived from the Greek word
“epigenesis” which originally
described the influence of
genetic processes on
development. Conrad H.
Waddington and Ernst Hadorn,
started the study of epigenetics.

16. • During the 1990s there became a renewed
interest in genetic assimilation. This lead to
elucidation of the molecular basis of Conrad
Waddington’s observations in which
environmental stress caused genetic
assimilation of certain phenotypic characteristics
in Drosophila fruit flies. Since then, research
efforts have been focused on unravelling the
epigenetic mechanisms related to these types of
changes.

17. • Currently, DNA methylation is one of the most
broadly studied and well-characterized
epigenetic modifications dating back to studies
done by Griffith and Mahler in 1969 which
suggested that DNA methylation may be
important in long term memory function.

18. How do Epigenetics work?

19. • An epigenome consists of a record of the
chemical changes to the DNA and histone
proteins of an organism; these changes can be
passed down to an organism's offspring.
Changes to the epigenome can result in
changes to the structure of chromatin and
changes to the function of the genome.

20. • The epigenome is a multitude of chemical
compounds that can tell the genome what to do.
The human genome is the complete assembly of
DNA (deoxyribonucleic acid)-about 3 billion base
pairs - that makes each individual unique.

21. • DNA holds the instructions for building the
proteins that carry out a variety of functions in a
cell. The epigenome is made up of chemical
compounds and proteins that can attach to DNA
and direct such actions as turning genes on or
off, controlling the production of proteins in
particular cells.

22. • When epigenomic compounds attach to DNA
and modify its function, they are said to have
"marked" the genome. These marks do not
change the sequence of the DNA. Rather, they
change the way cells use the DNA's instructions.
The marks are sometimes passed on from cell to
cell as cells divide. They also can be passed
down from one generation to the next.

24. • Epigenetic tags act as a kind of cellular
memory which have the sum of the signals it
has received during its lifetime.

26. The Changing Epigenome Informs Gene
Expression
• As a fertilized egg develops into a baby, dozens
of signals received over days, weeks, and
months cause incremental changes in gene
expression patterns. Epigenetic tags record the
cell's experiences on the DNA, helping to
stabilize gene expression.

27. • Each signal shuts down some genes and
activates others as it nudges a cell toward its
final fate. Different experiences cause the
epigenetic profiles of each cell type to grow
increasingly different over time. In the end,
hundreds of cell types form, each with a distinct
identity and a specialized function.

28. • Even in differentiated cells, signals fine-tune cell
functions through changes in gene expression. A
flexible epigenome allows us to adjust to
changes in the world around us, and to learn
from our experiences.

30. Early in development
Most signals come from within cells or from
neighboring cells. Mom's nutrition is also
important at this stage. The food she brings into
her body forms the building blocks for shaping
the growing fetus and its developing epigenome.
Other types of signals, such as stress hormones,
can also travel from mom to fetus.

31. After birth and as life continues
A wider variety of environmental factors start to
play a role in shaping the epigenome. Social
interactions, physical activity, diet and other
inputs generate signals that travel from cell to
cell throughout the body. As in early
development, signals from within the body
continue to be important for many processes,
including physical growth and learning.
Hormonal signals trigger big changes at puberty.

32. Mechanisms of Epigenetics
• DNA methylation
• Histone Modification
• Non-coding RNA (ncRNA)-
associated gene

33. DNA Methylation
• DNA methylation is an epigenetic mechanism used by
cells to control gene expression. A number of
mechanisms exist to control gene expression in
eukaryotes, but DNA methylation is a commonly used
epigenetic signaling tool that can fix genes in the “off”
position.

34. Histone Modification
• Histone modifications are proposed to affect
chromosome function through at least two
distinct mechanisms. The first mechanism
suggests modifications may alter the
electrostatic charge of the histone resulting in
a structural change in histones or their binding to
DNA.

35. Histone Modification
• The second mechanism proposes that these
modifications are binding sites for protein
recognition modules, such as the
bromodomains or chromodomains, that
recognize acetylated lysines or methylated
lysine, respectively.

37. Non-coding RNA (ncRNA)-associated gene
• ncRNA represent small RNA molecules encoded
in the genomes of plants and animals. These
highly conserved 22 nucleotides long RNA
sequences regulate the expression of genes by
binding to the 3'-untranslated regions (3'-UTR) of
specific mRNAs. A growing body of evidence
shows that ncRNAs are one of the key players in
cell differentiation and growth, mobility and
apoptosis (programmed cell death).

38. • ncRNAs regulate diverse aspects of
development and physiology, thus
understanding its biological role is proving more
and more important. Analysis of ncRNA
expression may provide valuable information, as
dysregulation of its function can lead to human
diseases such as cancer, cardiovascular and
metabolic diseases, liver conditions and immune
dysfunction.

40. Epigenetics and the Environment:
How Lifestyle Can Influence
Epigenetic Change from One
Generation to the Next

41. • The field of epigenetics is quickly growing and
with it the understanding that both the
environment and individual lifestyle can also
directly interact with the genome to influence
epigenetic change. These changes may be
reflected at various stages throughout a person’s
life and even in later generations.

42. • For example, human epidemiological studies
have provided evidence that prenatal and
early postnatal environmental factors
influence the adult risk of developing various
chronic diseases and behavioral disorders.

43. Epigenetic Inheritance

44. • It may be possible to pass down epigenetic
changes to future generations if the changes
occur in sperm or egg cells. Most epigenetic
changes that occur in sperm and egg cells get
erased when the two combine to form a fertilized
egg, in a process called “reprogramming.” This
reprogramming allows the cells of the fetus to
"start from scratch" and make their own
epigenetic changes.

45. • But scientists think some of the epigenetic
changes in parents' sperm and egg cells may
avoid the reprogramming process, and make it
through to the next generation. If this is true,
things like the food a person eats before they
conceive could affect their future child.

46. Epigenetics in Psychiatry

47. Anxiety and risk-taking
• In a small clinical study in humans published in
2008, epigenetic differences were linked to
differences in risk-taking and reactions to stress
in monozygotic twins. The study identified twins
with different life paths, wherein one twin
displayed risk-taking behaviours, and the other
displayed risk-averse behaviours.

48. Stress
• Animal and human studies have found
correlations between poor care during infancy
and epigenetic changes that correlate with long-
term impairments that result from neglect.
• Studies in rats have shown correlations between
maternal care in terms of the parental licking of
offspring and epigenetic changes. A high level of
licking results in a long-term reduction in stress
response as measured behaviourally and
biochemically in elements of the hypothalamic-
pituitary-adrenal axis (HPA).

49. Stress
• Further, decreased DNA methylation of the
glucocorticoid receptor gene were found in offspring
that experienced a high level of licking; the
glucorticoid receptor plays a key role in regulating
the HPA. The opposite is found in offspring that
experienced low levels of licking, and when pups are
switched, the epigenetic changes are reversed. This
research provides evidence for an underlying
epigenetic mechanism. Further support comes from
experiments with the same setup, using drugs that
can increase or decrease methylation.

50. Stress
• Finally, epigenetic variations in parental care can
be passed down from one generation to the
next, from mother to female offspring. Female
offspring who received increased parental care
(i.e., high licking) became mothers who engaged
in high licking and offspring who received less
licking became mothers who engaged in less
licking

51. Stress
• In humans, a small clinical research study
showed the relationship between prenatal
exposure to maternal mood and genetic
expression resulting in increased reactivity to
stress in offspring. Three groups of infants were
examined: those born to mothers medicated for
depression with serotonin reuptake inhibitors;
those born to depressed mothers not being
treated for depression; and those born to non-
depressed mothers.

52. Stress
• Prenatal exposure to depressed/anxious mood
was associated with increased DNA methylation
at the glucocorticoid receptor gene and to
increased HPA axis stress reactivity. The findings
were independent of whether the mothers were
being pharmaceutically treated for depression.

53. Learning and memory
• A 2010 review discusses the role of DNA
methylation in memory formation and storage,
but the precise mechanisms involving neuronal
function, memory, and methylation reversal
remain unclear.

54. Learning and memory
• Studies in rodents have found that the
environment exerts an influence on epigenetic
changes related to cognition, in terms of learning
and memory; environmental enrichment
correlated with increased histone acetylation,
and verification by administering histone
deacetylase inhibitors induced sprouting of
dendrites, an increased number of synapses,
and reinstated learning behaviour and access to
long-term memories.

55. Learning and memory
• In human studies, post-mortem brains from
Alzheimer's patients show increased histone de-
acetylase levels.

56. Addiction
• Environmental and epigenetic influences seem
to work together to increase the risk of addiction.
For example, environmental stress has been
shown to increase the risk of substance abuse.
In an attempt to cope with stress, alcohol and
drugs can be used as an escape. Once
substance abuse commences, epigenetic
alterations may further exacerbate the biological
and behavioural changes associated with
addiction.

57. Addiction
• Even short-term substance abuse can produce
long-lasting epigenetic changes in the brain of
rodents, via DNA methylation and histone
modification. Epigenetic modifications have been
observed in studies on rodents involving ethanol,
nicotine, cocaine, amphetamine,
methamphetamine and opiates.

58. Addiction
• Specifically, these epigenetic changes modify gene
expression, which in turn increases the vulnerability
of an individual to engage in repeated substance
overdose in the future. In turn, increased substance
abuse results in even greater epigenetic changes in
various components of a rodent's reward system
(e.g., in the nucleus accumbens). Hence, a cycle
emerges whereby changes in the pleasure-reward
areas contribute to the long-lasting neural and
behavioural changes associated with the increased
likelihood of addiction, the maintenance of addiction
and relapse.

59. Addiction
• In humans, alcohol consumption has been
shown to produce epigenetic changes that
contribute to the increased craving of alcohol. As
such, epigenetic modifications may play a part in
the progression from the controlled intake to the
loss of control of alcohol consumption. These
alterations may be long-term, as is evidenced in
smokers who still possess nicotine-related
epigenetic changes ten years after cessation.

60. Addiction
• Therefore, epigenetic modifications may account
for some of the behavioural changes generally
associated with addiction. These include:
repetitive habits that increase the risk of disease,
and personal and social problems; need for
immediate gratification; high rates of relapse
following treatment; and, the feeling of loss of
control.

61. Eating disorders and obesity
• Epigenetic changes may help to facilitate the
development and maintenance of eating
disorders via influences in the early environment
and throughout the life-span. Pre-natal
epigenetic changes due to maternal stress,
behaviour and diet may later predispose
offspring to persistent, increased anxiety and
anxiety disorders. These anxiety issues can
precipitate the onset of eating disorders and
obesity, and persist even after recovery from the
eating disorders.

62. Eating disorders and obesity
• Epigenetic differences accumulating over the
life-span may account for the incongruent
differences in eating disorders observed in
monozygotic twins. At puberty, sex hormones
may exert epigenetic changes (via DNA
methylation) on gene expression, thus
accounting for higher rates of eating disorders in
men as compared to women. Overall,
epigenetics contribute to persistent, unregulated
self-control behaviours related to the urge to
binge

63. Schizophrenia
• Epigenetic changes including hypo-methylation
of glutamatergic genes in the post-mortem
human brains of schizophrenics are associated
with increased levels of the neurotransmitter
glutamate. Since glutamate is the most
prevalent, fast, excitatory neurotransmitter,
increased levels may result in the psychotic
episodes related to schizophrenia.

64. Schizophrenia
• DNMT1 is selectively overexpressed in gamma-
aminobutyric acid (GABA)-ergic interneurons of
schizophrenic brains, whereas hyper-
methylation has been shown to repress
expression of Reelin (a protein required for
normal neurotransmission, memory formation
and synaptic plasticity) in brain tissue from
patients with schizophrenia and patients with
psychosis.

65. Schizophrenia
• Population studies have established a strong
association linking schizophrenia in children
born to older fathers. Specifically, children born
to elder fathers are up to three times more likely
to develop schizophrenia. Epigenetic dysfunction
in human male sperm cells, affecting numerous
genes, have been shown to increase with age.

66. Schizophrenia
• To this end, toxins (e.g., air pollutants) have
been shown to increase epigenetic
differentiation. Animals exposed to ambient air
from steel mills and highways show drastic
epigenetic changes that persist after removal
from the exposure.

67. Schizophrenia
• Schizophrenia studies provide evidence that the
nature versus nurture debate in the field of
psychopathology should be re-evaluated to
accommodate the concept that genes and the
environment work in tandem. As such, many
other environmental factors (e.g., nutritional
deficiencies and cannabis use) have been
proposed to increase the susceptibility of
psychotic disorders like schizophrenia via
epigenetics.[

68. Bipolar disorders
• Evidence for epigenetic modifications for bipolar
disorder is unclear. One study found
hypomethylation of a gene promoter of a
prefrontal lobe enzyme (i.e., membrane-bound
catechol-O-methyl transferase, or COMT) in
post-mortem brain samples from individuals with
bipolar disorder.
• COMT is an enzyme that metabolizes dopamine
in the synapse. These findings suggest that the
hypomethylation of the promoter results in over-
expression of the enzyme.

69. Bipolar disorders
• In turn, this results in increased degradation of
dopamine levels in the brain. These findings
provide evidence that epigenetic modification in
the prefrontal lobe is a risk factor for bipolar
disorder.

70. Major depressive disorder
• The epigenetic changes leading to changes in
glucocorticoid receptor expression and its effect
on the HPA stress system
• Also, much of the work in animal models has
focused on the indirect downregulation of brain
derived neurotrophic factor (BDNF) by over-
activation of the stress axis. Studies in various
rodent models of depression, often involving
induction of stress, have found direct epigenetic
modulation of BDNF as well.

71. Suicide
• A study of the brains of 24 suicide completers,
12 of whom had a history of child abuse and 12
who did not, found decreased levels of gluco-
corticoid receptor in victims of child abuse and
associated epigenetic changes

72. Thank You