Questions: Histone Modifications and Epigenetic Gene Regulation

Question 1

A researcher analyzes a gene's promoter region and finds high levels of H3K27me3. What does this predict about that gene's expression state?

• A. The gene is actively transcribed, because methylation generally opens chromatin
• B. The gene is silenced by the Polycomb repressive complex
• C. The gene is in an accessible euchromatin state ready for transcription
• D. The gene is undergoing active DNA replication at that site

Answer: (B)

H3K27me3 — trimethylation of lysine 27 on histone H3 — is a repressive mark placed by the Polycomb repressive complex. It signals silenced, compacted heterochromatin. This contrasts with H3K4me3 (trimethylation of lysine 4), which marks active promoters. The same modification type (methylation) has opposite effects depending on which residue it targets — position matters as much as the chemical group.

Question 2

How do histone acetyltransferases (HATs) promote gene transcription?

• A. By adding a positive charge to lysine residues, strengthening the histone grip on DNA
• B. By neutralizing the positive charge on lysine residues, weakening the electrostatic attraction to DNA and opening chromatin
• C. By recruiting Polycomb repressive complexes to compact the chromatin
• D. By methylating H3K27 to loosen nucleosome packing

Answer: (B)

Lysine residues on histone tails are positively charged, creating a strong electrostatic attraction to the negatively charged DNA backbone, which compacts chromatin. When HATs add an acetyl group, they neutralize this positive charge, weakening the histone-DNA grip and producing more open (euchromatin) chromatin that transcription machinery can access. This is why HAT activity correlates with gene activation, and HDAC (deacetylase) activity correlates with silencing.

Question 3

Two daughter cells produced by mitosis can maintain different gene expression patterns from their parent cell without any change to their DNA sequence, because histone modification patterns can be copied onto newly assembled nucleosomes during replication.

• T. True
• F. False

Answer: True

This is the essence of epigenetic inheritance. When a cell divides, histone-modifying enzymes are recruited to newly assembled nucleosomes and re-establish the parent cell's modification pattern. This allows liver cells to keep producing liver-specific proteins and neurons to maintain neuron-specific expression, even though both cell types carry identical DNA. Cellular identity is maintained through this molecular memory without any change to the genetic sequence.

Question 4

Histone methylation is typically a repressive modification — wherever it occurs in the genome, it signals that a gene should be silenced.

• T. True
• F. False

Answer: False

This is a critical misconception. H3K4me3 marks active gene promoters and is associated with gene activation, while H3K27me3 marks genes silenced by Polycomb complexes, and H3K9me3 marks constitutive heterochromatin. Even H3K36me3 marks actively transcribed gene bodies. The same chemical modification — adding methyl groups — produces opposite effects depending on which lysine residue on which histone it targets. Position specificity is the key to reading the histone code.

Question 5

Why are histone modifications considered 'epigenetic' rather than 'genetic,' and why does their heritability make them biologically significant?

Model answer: Histone modifications are epigenetic because they alter gene expression without changing the underlying DNA sequence. A genetic change alters the nucleotide sequence; an epigenetic change alters how that sequence is accessed. Heritability is significant because it allows cells to maintain distinct identities across divisions — a liver cell passes its histone modification pattern to daughter cells, preserving liver gene expression without needing to re-establish which genes to activate after every division.

The distinction matters because it reveals a layer of information above the DNA sequence. Two cells with identical genomes can have radically different phenotypes because of their epigenetic states. This also explains why drugs targeting histone-modifying enzymes (like HDAC inhibitors in cancer therapy) can reverse aberrant gene silencing without altering the patient's DNA.