Epigenome
• The genome is a sequence of nucleotides that is
Exploring Your Genome
Week 9 : Epigenomics
Lecture 1: Introduction
The epigenome is the answer to many
big questions
• How does one genome result in so many
different cells and developmental stages?
• How can two people with the same exact
genome (twins) develop radically different
functional outcomes (phenotypes)?
• How can environmental exposure in
parents lead to heritable, but non-
nucleotide, changes in future generations?
First, let’s review Chromatin
Chromatin is the complex of DNA and its
associated proteins
The proteins are mostly histones
transmitted to the next generation
• The epigenome is the unique collection of modifications to
the nucleotides and associated proteins
• These modifications control access to the genome itself
• The epigenome is another level of genetic information
• “Epi” is Greek for on, above, near
Epigenomics: The Next Frontier
• Building on the Human Genome Project
• Epigenome refers to the genome-wide
distribution of all modifications to
chromatin in a cell
• Epigenetics is the study of heritable
changes in gene function that are not due to
a change in DNA sequence (different
phenotypes, same genotype)
Chromatin in Eukaryotic cells
DNA is packed by wrapping around histone proteins
 Packed DNA and histones form DNA in the densely packed state is not usually transcribed
because the transcriptional machinery cannot access the
nucleosomes DNA
DNA packing is a method of gene expression control: packed
DNA = unreadable genes; open DNA = readable genes

Histone proteins have short “tails”

Epigenetic marks are modifications that are made to the DNA

or to the histones Epigenetic marks
The modifications can be proteins or chemical groups. They
attach to the nucleotides directly or to the histone tails
• The marks, or modifications, occur normally
throughout a lifetime
• The marks help to control access to the
genes - turning genes on/off through
different stages of development and
differentiation

1. Methylation
Main types of epigenetic mechanisms
• The best known and best studied type of epigenetic
1. Methylation of Cytosines modification
2. Histone tail modification • Methylation of DNA has been studied for years
• DNA and histones can both be methylated
3. Chromatin binding proteins
• Used as method to regulate gene expression
4. Non-coding RNAs • Typically, methylation of DNA blocks transcription and
represses expression

There are other types, but these are the main ones.
Discovering new mechanisms of epigenetic control is a
HOT area of research.
 Methylation 2. Histone Modification
• Cytosines in CG rich regions are the targets of
methylation (CGCGGGCCGCCGC)
• CG rich regions are near mammalian genes
• Methyl group is added to cytosines
• Methylated cytosine prevents gene expression by
blocking access of transcriptional machinery or by
condensing the DNA

Histone tails are targets of modification.

Chemical groups attach to the tails and help
to repress or activate transcription of DNA

3. Chromatin binding proteins

Until recently, these two
There are proteins that
mechanisms of epigenetics
bind to the epigenetic
were the only ones
marks like methylated
studied. There has been
bases and help to repress
a boom in epigenetic or activate transcription.
research in the past few
years.

4. Non-coding RNA
Non-coding RNAs are small RNA
sequences that do NOT code for Normal Epigenetic Roles
proteins. They were recently discovered
in the HG. Remember, that much of the
HG is transcribed into RNA but not
translated. Perhaps the “Junk” DNA is • X-inactivation
part of the epigenetic mechanism. Non- • Cell differentiation
coding RNAs have been identified as
helping to keep DNA in a tightly wound • Imprinting
structure.
• Gene regulation in response to
Non-coding RNAs play
a role in X-
environmental factors
inactivation. Here, the
Xist RNA coats the X
chromosome to keep it
inactive.
 Epigenetics plays a role in tissue differentiation
• All cells have the same DNA - but how do they
develop many specialized instructions?
• Specialized cells result from a precise
combination of genes being turned on/off at the
right time
• Tightly coordinated gene regulation is critical
• Epigenetic marks create a “cell memory” so that
the daughter of a skin cell remembers to be a skin
cell
Every cell has its own unique epigenetic
“fingerprint”
The fingerprints can change during aging, disease
(particularly cancer), and in response to
environmental factors
Imprinting
Cell Memory
• Daughter cells of differentiated cells must
pass on not only the DNA sequence, but the
epigenetic marks that tell which genes to
turn on
• It is not known how these epigenetic marks
survive the process of cell division and are
transmitted successfully to daughter cells
• This is a major area of research
Imprinting
• Epigenetic marks made during embryonic development
• Imprinting is a normal part of animal development
• A paternal chromosome may be imprinted differently than
the homologous maternal chromosome
• Imprinted genes or chromosomal regions, are ones in
which either the maternal or paternal copy is activated and
the other one is silenced. This is non-random silencing.
• Another big area of research is which mechanisms the cell
uses to silence entire chromosomes (ie, X inactivation)
versus how to silence specific genes or chromosomal
regions
Methylation of genome occurs during normal
human development
 Genetic abnormalities in imprinted UBE3A gene is located on Chr. 15 and is
regions can result in medical disorders deleted in AS patients
• Prader-Willi and Angelman’s • Ubiquitin protein ligase E3A
Syndrome
• Two disorders caused by a
• Enzyme that targets proteins to be degraded
deletion in the same region on (normal process of cells)
Chr. 15 but they have very • We inherit two copies of UBE3A and both
different phenotypes
• The different outcomes depend
are usually active in most tissues of the
on if the maternal or paternal body
chromosome has the deletion
• In the brain, only the maternal version is
active

Loss of maternal UBE31gene on Loss of paternal version of Chr. 15

Chr 15 function results in AS
• Gene function can be lost by: deactivation of gene,
mutations in gene, shortened protein,
chromosomal deletions or rearrangements
• Because the paternal version of UBE31 on Chr 15
is normally turned off, no functional UBE31 is
produced in the brain
• Symptoms: developmental delay, short attention
span, intellectual disability, recurrent seizures,
children have a happy, excitable, demeanor
marked by frequent smiling and hand flapping
region results in PW Syndrome
• Just like UBE3A is only active on the maternal
chromosome, other genes in the same region of Chr. 15
are only active on the paternal chromosome
• If the paternal version of the Chr. 15 region is missing, the
result is Prader-Willi Syndrome
• Symptoms: delayed development, mild to severe mental
disability, insatiable appetite that leads to obesity and type
2 diabetes

Imprinting in cloned animals Summary

Many cloning attempts are
unsuccessful
Many cloned animals have
unusual diseases
Dolly died at age 6 (normal
• The epigenome is the layer of modifications to the genome
• Epigenetics refers to the inheritance of a gene function or phenotype that is not due to a
nucleotide change
• Epigenetic marks are common throughout the genome.
• Epigenetic marks help to activate specific genes during differentiation.
• Each cell has its own unique epigenetic fingerprint.

lifespan is 12). She had cancer
and arthritis - 2 illnesses that
were more common in elderly
sheep
One reason why cloned
animals may have problems is
because their genomes are not
imprinted properly
• The four main types of epigenetic mechanisms are: methylation, histone modification,
chromatin regulator proteins, and non-coding RNA
• Methylation is the most common type of epigenetic mark.
• Imprinting is the establishment of epigenetic patterns on either the maternal or paternal
versions of those genes
• Genetic alterations in imprinted regions of the genome can result in medical disorders
because both gene copies are silenced or defective