Epigenetics = Heritable changes in cellular function or gene expression transmitted cell-to-cell (or generation-to-generation) via chromatin-based molecular signals — without altering the DNA sequence.
Epigenomics = Genome-wide study of epigenetic patterns (methylome, histone landscapes, nucleosome positioning across cell types).
🧠 Memory Trick
"Epi = Above" — Think of it as notes written on top of the DNA without changing the letters. Like sticky notes on a textbook — the book stays the same, but the notes change how you read it!
Two Key Properties
⚡
Dynamic & Transient Rapid response to cell needs
OR
🔒
Long-lasting Transmitted through cell divisions / generations
The Big 3 Mechanisms
Fig: The three major epigenetic mechanisms (Fig. 3-8)
🧠 Mnemonic: "MoMoVa"
Methylation (DNA) · Modifications (Histones) · Variants (Histones) Key distinction from genetics: epigenetic marks are sequence-independent
Clinical
Environmental/lifestyle factors alter epigenetic marks → disease. Reversibility = therapeutic opportunity. Large-scale projects: ENCODE, methylome catalogues.
2
DNA Methylation
Methylation of cytosine C5 (carbon 5 of the pyrimidine ring) → produces 5-methylcytosine (5-mC). Occurs almost exclusively at CpG dinucleotides.
Methyl-CpG binding proteins
→
Recruit chromatin-modifying enzymes
→
SILENCE transcription
5-mC vs 5-hmC
5-mC
(methylcytosine) Stable mark, inherited through cell division ~5% of all cytosines
vs
5-hmC
(hydroxymethylcytosine) Variable; highest in regulatory regions 0.1–1% of cytosines Likely demethylation intermediate
🧠 Memory Trick
"Methylation = Mute" — Both start with M. Methylate a gene → mute/silence it! "CpG = C-phosphate-G" — The p is the phosphodiester bond between C and G.
Demethylation: 5-mC → 5-hmC (enzymatic). Extensive demethylation during germ cell development & early embryogenesis (restores totipotency/pluripotency).
Clinical
Cancer: hypomethylation of large genomic segments OR regional hypermethylation at CpG islands (Ch. 15). Differential methylation at specific loci + sequence variation → modulates genetic risk (e.g., rheumatoid arthritis).
3
Histone Modifications & Variants
Modifications occur on N-terminal "tails" of core histones H2A, H2B, H3, H4, extending from the nucleosome core (Fig. 3-8).
Key Modification Types
Methylation
Acetylation
Phosphorylation
Must-Know Marks
Mark
Example
Effect
H3K9 methylation
H3K9me
Repressive — silent chromatin
H3K27 acetylation
H3K27ac
Activating — open regulatory regions
🧠 Memory Trick
"K9 silences like a K-9 police dog guarding the gene" — H3K9me = repressive! "Acetylation = Activation" — Both start with "A"! H3K27ac = active.
Histone tails protruding from nucleosome with modifications
ENCODE Project: identified 12 common modifications across ~50 cell types, attributing putative function to >50% of the genome — far more than the ~2% that is "coding."
Histone Variants
Encoded by separate genes; replace core histones to generate specialized chromatin.
Variant
Location
Function
CENP-A
Centromeres only
Marks kinetochore location
H2A.X
Sites of DNA damage
Marks DSBs requiring repair
🧠 Memory Trick
"CENP-A = CENter Piece" — sits at the center (centromere) of the chromosome. "H2A.X = X marks the spot" — X marks the damage!
4
Chromatin Architecture & 3D Genome
The genome is NOT a linear string — it adopts a highly ordered 3D arrangement in the nucleus, guided by epigenetic signals. The 3D landscape predicts the transcriptome of any cell type.
Four Levels of Organization
Level
Feature
Significance
Chromosome territories
Each chromosome occupies a distinct nuclear territory
Bring enhancers/locus-control regions to promoters
Long-range gene activation
Nucleosome positioning
Gaps between nucleosomes expose DNA
TF and regulatory protein binding
Chromosome territories and chromatin loops within the nucleus (Fig. 3-10)
🧠 Memory Trick — "TSLN" (Top → Small)
Territories → Subchromosomal domains → Loops → Nucleosome positioning Think: "This Structure Lets Nature" organize genes in 3D
5
Allelic Imbalance in Gene Expression
Genes present in two copies are not always expressed equally from both alleles. Three major patterns:
Three patterns of allelic expression (Fig. 3-11)
Prevalence: 5–20% of autosomal genes show unequal expression; usually <2-fold, but up to 10-fold differences seen.
Cause: Sequence variants alter TF binding or DNA methylation patterns at the two alleles.
🧠 Memory Trick
Think of it as a volume knob: Balanced = both speakers equal, Imbalanced = one speaker louder, Monoallelic = one speaker completely off.
6
Monoallelic Expression: 4 Mechanisms
Four distinct ways a cell can express only one of its two alleles (Table 3-2):
Type
Genes
Basis
Origin
Somatic rearrangement
Immunoglobulins, T-cell receptors
DNA cutting & pasting → functional gene on one allele only
B- & T-cell lineages
Random monoallelic silencing
Olfactory receptors; up to 10% of genes in some cell types
Differential epigenetic packaging at locus
Specific cell types
Genomic imprinting
>100 developmental genes
Imprinted region epigenetically marked by parent of origin in germline
Parental germline
X chromosome inactivation
Most X-linked genes in females
Epigenetic silencing of one entire X chromosome
Early embryogenesis
Comparison of four monoallelic expression mechanisms (Table 3-2)
🧠 Mnemonic: "SRIX" (like "S-R-I-X")
Somatic rearrangement · Random silencing · Imprinting · X inactivation Only "S" changes DNA. The rest are epigenetic!
Key distinctions:
Somatic rearrangement: UNIQUE — only in B & T cells, rearranges actual DNA. Rearranges hundreds of kilobases. Mature Ig/TCR mRNA is exclusively monoallelic.
Random monoallelic: broadens diversity of cellular responses (e.g., 1 OR gene per olfactory sensory neuron from among hundreds of family members). Also seen in immune/chemosensory genes.
7
Genomic Imprinting
Imprinting = Monoallelic expression determined nonrandomly by parental origin. Epigenetic marks established in the germline of one parent.
Core Features
Occurs during gametogenesis, before fertilization
After fertilization, imprint maintained through hundreds of somatic cell divisions
Must be reversible: paternally-imprinted allele inherited by a female → must be converted to maternal imprint in her germline for the next generation
Controlled by imprinting control regions (imprinting centers) — often involve ncRNAs that initiate epigenetic changes spreading outward along the chromosome
Confined to a delimited genomic segment (few hundred kb to few Mb) — distinct from random monoallelic expression (individual genes) or X-inactivation (whole chromosome)
The imprinting cycle: set → maintain → reset
🧠 Memory Trick
"Imprint = Stamp from parent" — Like a wax seal on a letter. Mom stamps some genes, Dad stamps others. The seal is removed and re-stamped each generation.
vs Random monoallelic: Imprinting is NOT random — it's always the same parent's allele silenced. Like a rule vs a coin flip.
Most extensive example of random monoallelic expression. Mechanism of dosage compensation in females — silences most genes on one X chromosome.
Key Steps
Early embryogenesis (first week)
→
Random choice per cell
→
Clonally maintained all daughter cells
→
Female = clonal mosaic
X inactivation creates a clonal mosaic in females (Fig. 3-13)
Epigenetic Features of Inactive X
DNA methylation
Histone modifications
macroH2A variant
Inactive X = Barr body (heterochromatic mass visible in interphase nuclei).
Exceptions!
At least 15% of X-linked genes show biallelic expression (active on both Xi and Xa)
Pseudoautosomal genes (identical on X & Y) show balanced biallelic expression and do NOT inactivate
🧠 Memory Tricks
"XIST = eXit sign for X" — XIST RNA coats the X and tells it to shut down (exit)! "Barr body = Barred from expression" — The Barr body is the inactive X, barred from being read. "Calico cats" — Classic example of X-inactivation mosaic. Orange/black patches = different X active in each clone!
Clinical
Carrier females for X-linked disease show variable phenotype depending on the ratio of Xi vs Xa cells (Ch. 6, 7). Skewed inactivation can cause symptomatic carriers.
🃏 Flashcard Deck
Click any card to flip it. Score: 0/40 reviewed
Topic 1: Overview
What is epigenetics?
Heritable changes in cellular function or gene expression via chromatin-based molecular signals WITHOUT altering the DNA sequence. Transmitted cell-to-cell or across generations.
Name the 3 major epigenetic mechanisms
1) DNA methylation (repression) 2) Histone modifications (activation or repression) 3) Histone variants (mark specific regions)
Two key properties of epigenetic changes?
1) Dynamic & transient (rapid response) 2) Long-lasting (transmitted through cell divisions or generations)
What is epigenomics?
Genome-wide study of epigenetic patterns: methylome, histone landscapes, nucleosome positioning across cell types.
Topic 2: DNA Methylation
Where does DNA methylation occur?
Cytosine C5 (carbon 5 of the pyrimidine ring) → 5-methylcytosine (5-mC). Almost exclusively at CpG dinucleotides.
5-mC: stable mark, ~5% of all cytosines in adults, inherited through division. 5-hmC: variable, 0.1-1% of cytosines, highest in regulatory regions. Likely demethylation intermediate.
When does extensive demethylation occur?
During germ cell development & early embryogenesis — restores totipotency/pluripotency. 5-mC → 5-hmC → unmethylated C.
DNA methylation changes in cancer?
Hypomethylation of large genomic segments OR regional hypermethylation at CpG islands. Both common patterns.
Topic 3: Histone Modifications & Variants
Where do histone modifications occur?
On N-terminal "tails" of core histones H2A, H2B, H3, H4 extending from the nucleosome core.
H3K9me — activating or repressive?
REPRESSIVE — marks silent chromatin. 🧠 "K-9 police dog guards (silences) the gene"
H3K27ac — activating or repressive?
ACTIVATING — marks open regulatory regions. 🧠 "Acetylation = Activation" (both start with A)
What is CENP-A?
H3-related histone VARIANT found only at centromeres. Marks kinetochore location. 🧠 "CENP-A = CENter Piece"
What is H2A.X?
Histone variant that marks sites of DNA double-strand breaks requiring repair. 🧠 "X marks the (damage) spot"
ENCODE Project finding about histone modifications?
12 common modifications across ~50 cell types → putative function for >50% of the genome (far more than ~2% that codes for protein).
Topic 4: 3D Genome
Name the 4 levels of chromatin organization (big → small)
Bring enhancers/locus-control regions physically close to promoters → enable long-range gene activation.
Why is nucleosome positioning important?
Gaps between nucleosomes expose DNA → allow TF and regulatory protein binding.
Topic 5: Allelic Imbalance
What are the 3 patterns of allelic expression?
1) Balanced biallelic (G ≈ A) 2) Allelic imbalance (G > A) 3) Monoallelic (A only)
What % of autosomal genes show unequal expression?
5–20% show unequal expression; usually <2-fold difference, but up to 10-fold possible.
What causes allelic imbalance?
Sequence variants that alter TF binding or DNA methylation patterns at the two alleles.
Topic 6: Monoallelic Expression
Name the 4 mechanisms of monoallelic expression
SRIX: 1) Somatic rearrangement (DNA-level) 2) Random monoallelic silencing 3) Imprinting 4) X inactivation (Only #1 changes DNA; rest are epigenetic)
Which monoallelic mechanism actually changes DNA?
ONLY somatic rearrangement (Ig & TCR genes in B & T cells). The other three are purely epigenetic.
Random monoallelic silencing — classic example?
Olfactory receptors — one OR gene expressed per olfactory sensory neuron from among hundreds of family members. Also seen in immune/chemosensory genes. Up to 10% of genes in some cell types.
Topic 7: Genomic Imprinting
What is genomic imprinting?
Monoallelic expression determined NONRANDOMLY by parental origin. Epigenetic marks set in the germline of one parent.
When are imprints established?
During GAMETOGENESIS (before fertilization). Maintained through somatic cell divisions. Must be REVERSIBLE each generation.
What controls imprinting at a locus?
Imprinting control regions (imprinting centers) — often involve ncRNAs that initiate epigenetic changes spreading outward along the chromosome.