2. Mutations in the Histone Substrate: "Oncohistones"

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2.            Mutations in the Histone Substrate: "Oncohistones"

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2.            Mutations in the Histone Substrate: "Oncohistones"

H3K27M Mutations

Mechanistic Contrast

Where do the distinct class of mutations occur that affect PcG function

Not in the PcG proteins themselves, but in their substrate, Histone H3.

What is the specific mutation called H3K27M

A missense mutation changing Lysine 27 to Methionine.

In which type of cancer are H3K27M mutations typically found

Pediatric diffuse intrinsic pontine gliomas (DIPG).

In how many alleles do H3K27M mutations occur in DIPG

In a single allele.

Which histone genes are affected by H3K27M mutations

H3.3 (H3F3A) or H3.1 (HIST3H1B).

How does the mechanism of H3K27M oncohistones differ from EZH2 gain-of-function mutations

Unlike EZH2 GoF mutations which increase methylation, H3K27M oncohistones act in a dominant-negative manner to inhibit PRC2 enzymatic activity globally.

How does the H3K27M mutation inhibit PRC2 activity

The Methionine residue binds to and sequesters the EZH2 SET domain, preventing it from methylating wild-type histones.

What is the global effect of H3K27M mutations on the repressive H3K27me3 mark

A global loss of the repressive H3K27me3 mark.

What paradoxical effect occurs alongside the loss of H3K27me3 in H3K27M mutants

Increased active mark H3K27ac at many loci.

What is the ultimate consequence of H3K27M mutations on gene expression

Aberrant gene activati