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'K-to-M' histone mutations: How repressing the repressors may drive tissue-specific cancers
Date:8/29/2014

istone lysines with one or more methyl groups, which silences gene expression by squeezing associated DNA into an impenetrable coil.

"Previously scientists knew that mutations in methylating enzymes like PRC2 occur in some cancers," says Shilatifard. "What was surprising here was finding that mutation in one of the copies of the histone H3 gene, one of the proteins that PRC2 modifies, is associated with cancer. To figure out how that happened, we were interested in developing an in vivo model for the process in systems that we can study."

The team first engineered a version of histone H3.3 that mimicked the K27-to-M mutation and then inserted that construct into embryonic fly tissues to produce the damaged protein in a living fruit fly. Using antibodies that recognize methylated lysines, they discovered that a dose of the mutant protein was sufficient to decrease global methylation of normal histone H3.3 proteins at K27, just as loss of the PRC2 repressor would. When the group engineered a similar K-to-M mutant at lysine 9 (K9), they saw similar results. This analysis of the H3K27 and H3K9 mutants confirmed in vivo that K-to-M mutations in histone H3.3 repress a key repressor, PRC2, but did not nail down how this happened.

"One question was whether a single amino acid change like this could alter the way histone H3.3 interacts with other proteins," says Marc Morgan, Ph.D., a co-first author of the paper, "The mutant could be either losing or gaining something." To determine which, the group collaborated with the Stowers Proteomics Center to compare factors binding to normal histone H3.3 versus the K-to-M mutants using mass spectrometry.

That analysis revealed that the presence of mutant histones globally dampens histone interactions with some of the usual repressor suspects. But in what Morgan calls an "Aha!" moment, they detected promiscuous association of a demethylase called KDM3B with the histone H3K9 mutant. "This su
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Contact: Kim Bland, Ph.D.
ksb@stowers.org
816-926-4015
Stowers Institute for Medical Research
Source:Eurekalert  

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