Special Topics in

Modern Genetics 1
Epigenetics
Dr. Tamer Salem
Biomedical Sciences

Principles of Genetics
BMS 203
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 Introduction

 An epigenetic trait results from changes in gene expression

without alterations in the DNA sequence.
 Epigenetics is the study of the ways these changes alter cell-
and tissue-specific patterns of gene expression.
factors that affect gene expression

 The epigenome refers to the epigenetic state of a cell.

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 Epigenetic Alterations to the Genome

 There are three major epigenetic mechanisms:

– Reversible modification of DNA by addition/removal of

methyl groups.

– Alteration of chromatin by addition/removal of chemical

groups to histone proteins.

– Regulation of gene expression by small, noncoding RNA

molecules.

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 Methylation

 In mammals, methylation of the DNA takes place after replication and

during differentiation of adult cells.
– Involves the addition of methyl group (-CH3) to cytosine.
– Takes place almost exclusively on cytosine bases located adjacent to
a guanine base forming a CpG dinucleotide.
– Clustered in regions called CpG islands located in/near promoter
sequences adjacent to genes.
– Unmethylation makes genes available for transcription.

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 Histone Modification and Chromatin
Configuration
 Histone modification is an important
epigenetic mechanism of gene regulation.

 Chromatin is composed of DNA wound around

a core of eight histone proteins to form
nucleosomes.
 Amino acids in the N-terminal region of the
histones can be covalently modified by
acetylation, methylation, and
phosphorylation.

 These modifications alter the structure of

chromatin and make genes
accessible/inaccessible for transcription.

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 Histone Modification and Chromatin
Configuration
 Histone acetylation makes genes on modified nucleosomes available for
transcription.

 This modification is reversible and acetyl groups can be removed,

changing the chromatin from an “open” to a “closed” configuration,
silencing genes by making them unavailable.

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 MicroRNAs

 MicroRNAs (miRNAs) also participate in epigenetic regulation

of gene expression.
– Involved in controlling the pattern of developing embryos
and in the timing of developmental events and
physiological processes such as cell signaling
– Also play roles in the development of cardiovascular
disease and cancer

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 MicroRNAs

 miRNAs are transcribed as precursor molecules about 70–

100 nucleotides long, containing a double-stranded stem
loop.

 Forming a mature RNA-

Induced Silencing Complex
(RISC)

 RISCs act as
posttranscriptional repressors
of gene expression by binding
to and destroying target mRNA .
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http://jonlieffmd.com/
 MicroRNAs

 miRNA molecules can also associate with different

protein complexes to form RNA-Induced
Transcriptional Silencing (RITS) complexes.
 RITS complexes convert euchromatic chromosome
regions into facultative heterochromatin, which
silences genes located within these newly created
heterochromatic regions.
– This is reversible and can be converted to
euchromatin, which is accessible for transcription.
https://www.youtube.com/watch?v=_-9pROnSD-A

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 Epigenetics and Imprinting

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 Epigenetics and Imprinting

 Usually both maternal and paternal genes are

expressed in the offspring.
 Imprinting is an epigenetically regulated process in
which genes are expressed in a parent-of-origin
pattern.
– Expression of either maternal or paternal genes

 This parent-specific pattern of allele expression

occurs during gamete formation.

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 Epigenetics and Imprinting

 Differential methylation of CpG-rich regions and

promoter sequences produce allele-specific
imprinting and subsequent gene silencing.

 Once a gene has been imprinted, it remains

transcriptionally silent during embryogenesis and
development.

 Most imprinted genes direct aspects of growth during

prenatal development.
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 Epigenetics and Imprinting

 Having only one functional allele makes imprinted

genes highly susceptible to the deleterious effects
of mutations.

 Mutations in imprinted genes can arise by changes

in the DNA sequence or by dysfunctional epigenetic
changes, called epimutations (both are heritable
changes in the activity of a gene).

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 Epigenetics and Imprinting

 The pattern of imprinting in mammals is

reprogrammed every generation.

 When gamete formation begins in

female/male germ cells, both chromosome
sets have their imprints erased and
reprogrammed.

 Imprinted alleles remain transcriptionally

silent in all cells, while genes silenced by
epigenetic methylation can be reactivated
after differentiation.
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 Epigenetics and Cancer

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 Epigenetics and Cancer

 For some complex diseases, there are strong links

for environmental factors such as smoking and lung
cancer.
 In the 1980s Feinberg and Vogelstein observed that
colon cancer cells had much lower levels of
methylation than normal cells derived from the same
tissue.
 Complex changes in DNA methylation patterns are
associated with cancer.

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 Epigenetics and Cancer

 Global genomic hypomethylation is a property of all cancers to date.

 Selective hypermethylation and gene silencing are also properties of

cancer cells.
 Cancer is now viewed as a disease that involves both epigenetic and
genetic changes that lead to alterations in gene expression and the
development of malignancy.

 DNA hypomethylation
reverses the inactivation of
genes, leading to
unrestricted transcription of
many gene sets including
oncogenes.

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 Epigenetics and Cancer

 Hypermethylated genes include those involved in

DNA repair, differentiation, apoptosis, and drug
resistance.

 The majority of hypermethylated genes in cancer

cells are not tumor-suppressor genes.
– The pattern of hypermethylation may result from a
widespread deregulation of the methylation process
rather than a targeted event.

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 Epigenetics and Cancer

 Cancer cells also show disrupted histone modification

profiles.

 Mutations in the genes of the histone-modifying proteins

such as histone acetyltransferase (HAT) and histone
deacetylase (HDAC) are linked to the development of
cancer.

 The fact that methylation patterns occur very early in the

transformation process has led to the proposal that
epigenetic changes leading to cancer may occur within
adult stem cells in normal tissue.
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 Epigenetics and Cancer

 Three lines of evidence support stem cell

involvement in epigenetic changes:
– First: Epigenetic changes can replace mutation in
silencing individual tumor-suppressor genes or
activating oncogenes.
– Second: Global hypomethylation may cause genome
instability and the large-scale changes characteristic of
cancer.
– Third: Epigenetic modifications are more effective than
mutations in transforming normal cells into malignant
cells.

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 Epigenetics and Cancer

 A model of cancer based on epigenetic changes in

colon stem cells as initiating events in
carcinogenesis, followed by mutational events.

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 Epigenetics and Cancer

 The focus of epigenetic therapy is the reactivation of

genes that have been silenced by methylation or
histone modification.

 FDA has approved a drug (decitabine, marketed as

Vidaza) for treatment of acute myeloid leukemia.

 The first HDAC inhibitor, vorinostat (Zolinza), has

been approved for treatment of some forms of
lymphoma.
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 Epigenetics and the Environment

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 Epigenetics and the Environment

 Environmental agents (including nutrition,

chemicals, and physical factors such as
temperature) can alter gene expression by affecting
the epigenetic state of the genome.

 There is indirect evidence that changes in nutrition

and exposure to agents that affect the developing
fetus can have detrimental effects during adulthood.

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 Epigenetics and the Environment

 Women pregnant during the 1944–1945 famine in

the Netherlands had children with increased risk of
obesity, diabetes, and coronary heart disease.
– As adults, these individuals had significantly
increased risks for schizophrenia and other
neuropsychiatric disorders.
 The F2 generation also had abnormal patterns of
weight gain and growth.
 Similar results were found in adult children of
Chinese women pregnant during the 1959–1961
famine.
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 Epigenetics and the Environment

 The most direct evidence of environmental factors

modifying the epigenome comes from studies in
experimental animals.

 A low-protein diet fed to pregnant rats resulted in

permanent changes in the genes of both F1 and F2
offspring.
– Increased expression of liver genes is associated with
hypomethylation of their promoter regions.
– Epigenetic changes triggered by this modification were
gene specific.
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 Epigenetics and the Environment

 A dramatic example of how epigenome modifications

affect the phenotype comes from the study of coat
color in mice which is controlled by a dominant allele
Agouti (A).
– Homozygous AA mice: gene active only during a
specific time of hair development (yellow band on a
black hair shaft resulting in agouti phenotype).
– A nonlethal mutant allele (Avy) causes yellow pigment
formation along the entire hair shaft (producing yellow
fur color).

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 Epigenetics and the Environment

 This Avy allele is the result of the insertion of a transposable

element near the transcription start site of the Agouti gene.
– Promoter element within the transposon causes change in gene
expression.
 The degree of methylation in the transposon’s promoter is
related to the amount of yellow pigment and varies from
individual to individual.
– Variation in coat color phenotypes even in genetically identical mice.
– Also show gradation in body weight
– Yellow mice more obese than brown mice

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 Epigenetics and the Environment

 To evaluate the role of environmental factors in

modifying the epigenome, the diet of pregnant Avy
mice was supplemented with methylation precursors,
including folic acid, Vitamin B12, and choline.
– Variation in coat color in the offspring was reduced and
shifted to pseudoagouti (highly methylated) phenotype.

 It has been recently discovered that some foods such

as rice, cabbage, wheat, and potatoes are the source
of miRNAs circulating in the blood and serum of
humans.
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 Epigenome Projects

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 Epigenome Projects

 The NIH Roadmap Epigenomics Project is based

on the idea that many aspects of health and
susceptibility to disease are related to epigenetic
regulation or misregulation of gene activity.

 The NIH Roadmap Project is focused on how

epigenetic mechanisms controlling stem cell
differentiation and organ formation generate
biological response (to external and internal stimuli)
that result in disease.
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 Epigenome Projects

 The Human Epigenome Project is a multinational,

public/private consortium established to identify,
map, and establish the functional significance of all
DNA methylation patterns in the human genome.
– Analysis may show that genetic responses to
environmental cues mediated by epigenetic changes
are pathways to disease.

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 References and aiding materials

 Essentials of Genetics, 8e Klug/Cummings/Spencer/Palladin.

 https://www.youtube.com/watch?v=Tj_6DcUTRnM

 https://www.youtube.com/watch?v=9AfBsTAQ8zs

 https://www.youtube.com/watch?v=M4boKud1MRk

 http://learn.genetics.utah.edu/content/epigenetics/imprinting/
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