ASSIGNMENT OF

BIOTECHNOLOGY
 CONTENTS
• Introduction and Definition
• Factor affecting epigenetics and Inheritance
• Mechanism
• Epigenetic phenomenon
• Cancer and epigenetics
• Diagnosis
• Therapies targeting epigenetic modification
• Future
EPIGENETIC BASIS OF
DISEASES
WHAT ARE EPIGENETICS?
 EPIGENETICS
• 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.
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)
• 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.
• 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.
HISTORY OF EPIGENETICS
• 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.
• 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
unraveling the epigenetic mechanisms related
to these types of changes.
• 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.
 How do Epigenetics work?
• 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.
• 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.
• 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.
• 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.
• Epigenetic tags act as a kind of cellular
memory which have the sum of the signals it
has received during its lifetime.
 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.
• 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.
• 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.
 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.
 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.
MECHANISM OF
EPIGENETICS
 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.
 Natural Roles of DNA Methylation
in Mammalian System
Imprinting
X chromosome inactivation
Heterochromatin maintenance
Developmental controls
Tissue specific expression controls
DNA Methylation and Other Human
Diseases
 Imprinting Disorder:
• Beckwith-Wiedemann syndrome (BWS)
• Prader-Willi syndrome (PWS)
• Transient neonatal diabetes mellitus (TNDM)
 Repeat-instability diseases:
• Fragile X syndrome (FRAXA)
• Facioscapulohumeral muscular dystrophy
 Defects of the methylation machinery:
•Systemic lupus erythematous (SLE)
•Immunodeficiency, centromeric instability and facial
anomalies (ICF) syndrome
 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.
• The second mechanism proposes that these
modifications are binding sites for protein
recognition modules, such as the
bromodomains or chromo domains, that
recognize acetylated lysine’s or methylated
lysine, respectively.
 Histone Modifications and Human
Diseases
• Coffin-Lowry syndrome is a rare genetic disorder
characterized by mental retardation and abnormalities
of the head and facial and other areas. It is caused by
mutations in the RSK2 gene (histone
phosphorylation) and is inherited as an X-linked
dominant genetic trait. Males are usually more
severely affected than females.
• Rubinstein-Taybi syndrome is characterized
by short stature, moderate to severe intellectual
disability, distinctive facial features, and broad
thumbs and first toes. It is caused by mutations
in CREB-binding protein (histone acetylation).
 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).
• 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 deregulation of its function can lead to
human diseases such as cancer, cardiovascular
and metabolic diseases, liver conditions and
immune dysfunction.
 Cancer epigenetics
• A common paradigm of cancer epigenetics is
hyper methylation of CpG island of tumor
suppressor gene promoter.
• Hyper methylated promoter DNA is
associated with virtually every type of human
tumor.
– With each type of tumor having own
signature of methylated genes.
 CANCER METHYLATED GENE

Prostate GSTP1

Renal VHL

MLH1 (mismatch repair

Colon and endometrial
gene)

Esophageal APC
• Global hypo methylation: overall in 5- methyl
cytosine content in the genome
– Found in premalignant and early stages of
some neoplasm.
– Important in tumor progression.
• Gene-specific hypomethylation:
– Often affect promoter region of proto-
oncogene and oncogene which are normally highly
methylated.
DNA Methylation and Cancer
Epigenetic Inheritance
• 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.
• 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.
Epigenetics in Psychiatry
 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.
 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.
• 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
 CONT…
correlated with increased histone acetylation, and
verification by administering histone deacetylase
inhibitors induced sprouting of dendrites, an
increased number of synapses, and reinstated
learning behavior and access to long-term
memories.
• In human studies, post-mortem brains from
Alzheimer's patients show increased histone
deacetylase levels.
 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.
 Bipolar disorders
• Evidence for epigenetic modifications for bipolar
disorder is unclear. One study found hypo
methylation 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 hypo methylation of the promoter results
in overexpression of the enzyme.
• 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.
 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 down regulation 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.
 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
glucocorticoid receptor in victims of child
abuse and associated epigenetic changes.
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