Epigenetics & Regulation of Gene Expression

Key Molecular Acronyms (DO NOW)

• $DNA$ → Deoxyribonucleic Acid (nuclear genome)

• $mtDNA$ → Mitochondrial Deoxyribonucleic Acid (circular genome in mitochondria)

• $RNA$ → Ribonucleic Acid (single-stranded nucleic acid)

• $rRNA$ → Ribosomal Ribonucleic Acid (structural & catalytic component of ribosomes)

• $mRNA$ → Messenger Ribonucleic Acid (transcript that carries genetic code to ribosome)

• tRNA→ Transfer Ribonucleic Acid (adapter that brings amino acids during translation)

Chromatin Architecture & Histones

• DNA length far exceeds nuclear diameter; compaction is achieved by wrapping around histone proteins.

  • 8 histone molecules (octamer) + ~146 bp DNA ⇒ nucleosome.

  • “Beads-on-a-string” nucleosome chain = chromatin.

• Chromatin states

  • Loosely coiled ⇒ euchromatin (interphase, active genes)

  • Super-coiled ⇒ chromosomes (mitosis/meiosis, transport form)

• Histone roles

  • Provide structural scaffold

  • Regulate gene accessibility (on/off switch via chemical tags)

Central Dogma Refresher

• Information flow: $DNA \xrightarrow{\text{transcription}} mRNA \xrightarrow{\text{translation}} \text{polypeptide}$

• Example triplet conversion

  • DNA fragment: $CTCACTCCCGTTGGAA$

  • mRNA (complementary w/ U): $GAGUGAGGGCAACCUU$

  • Codons built ⟶ amino acids (gly, ser, ala, asn in slide example)

• “A gene encodes a protein”; expression level depends on transcription + translation efficiency.

Epigenetics – Core Definition

• Literal: “epi” (on top of) + “genetics” → modifications on top of the genome.

• Syllabus wording: study of phenotypic expression of genes dependent on

  • Factors controlling transcription & translation during protein synthesis

  • Products of other genes

  • Environmental inputs

• Key insight: DNA sequence remains unchanged; expression pattern can be permanently or heritably altered.

Histone Modification (General)

• Alters specific amino acids in histone tails → conformational change.

• Conformation is copied during DNA replication ⇒ cell-type memory (prevents a specialised cell reverting to stem-cell state).

• Two major chemical tags discussed: acetyl groups and methyl groups (can be mono-, di- or tri-methyl).

Histone Acetylation (Subtype of Modification)

• Addition of an acetyl group $(-COCH_3)$ to lysine residues on histone tails.

• Consequences

  • Neutralises positive charge on lysine → weakens electrostatic attraction between histone and negatively charged DNA.

  • DNA wraps more loosely ⇒ open chromatin.

  • RNA polymerase more easily binds promoter ⇒ ↑ transcription ⇒ enhanced gene expression.

DNA Methylation & Demethylation

• Methylation

  • Addition of methyl group to cytosine within $CpG$ dinucleotides.

  • Blocks transcription factor / RNA polymerase binding → ↓ transcription.

  • Therefore inhibits gene expression (gene silencing).

• Demethylation

  • Enzymatic removal of these methyl marks.

  • Restores accessibility ⇒ ↑ transcription & translation ⇒ increased expression.

Environmental & Life-Stage Influences

• Epigenetic marks accumulate naturally with

  • Age

  • Cellular differentiation

• Modifiable by external factors

  • Severe stress (psychological or physical)

  • Nutritional status & specific dietary compounds (e.g., folate, B vitamins supplying methyl groups)

  • Toxins, pollutants, drugs (e.g., bisphenol A, nicotine)

• Marks are reversible; some can be transmitted trans-generationally (parental environment → offspring phenotype).

Quote & Analogy

• Geneticist Danielle Reed: “Things written in pen you can’t change (DNA). Things written in pencil you can (epigenetics).”

  • Interpretation

  • DNA sequence = permanent ink.

  • Epigenetic tags = erasable/rewritable pencil, allowing dynamic regulation without altering the script.

Examination Practice Hints

• “Consequence of adding a methyl group”

  • State: $\text{CH}_3$ addition at $CpG$ sites → RNA polymerase blocked ⇒ reduced transcription (2 marks).

• “Two examples of epigenetic factors”

  • e.g., chronic stress, maternal diet, cigarette smoke, heavy metals, UV exposure (2 marks – any two).

• “Gene B wrapped around Structure C (histone) but Gene A not”

  • Gene B tightly bound nucleosome = heterochromatin ⇒ low/no expression.

  • Gene A loosely bound or acetylated histone ⇒ euchromatin ⇒ actively transcribed.

  • Mention role of RNA polymerase accessibility & possible acetylation/methylation differences (4 marks).

Case Study Prompts (Independent Practice)

• 1. “Lick Your Rats”

  • Phenotypic difference: high-licking vs low-licking mother rats produce pups with differing stress responses.

  • Environmental factor: maternal grooming behavior.

  • Mechanism: altered DNA methylation of glucocorticoid receptor gene in hippocampus.

• 2. “Identical Twins”

  • Phenotypic divergence with age despite identical genome.

  • Factors: differential environments, diet, lifestyle.

  • Mechanism: accumulating discordant methylation & histone modifications.

• 3. “Nutrition & the Epigenome”

  • Phenotype: coat color & obesity in agouti mice.

  • Factor: maternal intake of methyl-donor nutrients (folate, choline).

  • Mechanism: methylation of agouti gene promoter.

Learning Intentions & Success Criteria (Self-Checklist)

• I can define epigenetics and distinguish it from genetic mutation.

• I can describe:

  • Histone modification in general.

  • Specific processes: histone acetylation, histone methylation, DNA methylation, DNA demethylation.

• I can explain real-world examples (rats, twins, nutrition) illustrating epigenetic influence on populations.

• Linking to “Science as a Human Endeavour”: modern biotech (bisulfite sequencing, ChIP-seq) enabled these discoveries, expanding our understanding of inheritance and disease potential.