# Project 3: Mechanisms of Methyltransferase Dysregulation by Oncohistones

> **NIH NIH P01** · ROCKEFELLER UNIVERSITY · 2020 · $270,959

## Abstract

PROJECT SUMMARY
SUMMARY: The broad goal of this project is to study the detailed molecular mechanisms by which histone
mutations associated with cancers perturb chromatin states, leading to disease. The next phase of this program
is driven by our recent work with the Allis lab revealing a vastly expanded landscape of putative oncohistone
mutations - over 4200 missense mutations in dozens of human cancers. Remarkably, the mutations occur in all
four of the core histones and in both the N-terminal tails and globular histone fold domains. The very large
number of newly identified oncohistones makes experimental characterization daunting. A key challenge is to
identify those mutations that act as potential cancer drivers from those that are merely a consequence of the
high mutation burden of a given tumor (i.e. passengers). We will work closely with other members of the P01
team to identify those mutations that most likely to fall into the former category and that, as such, merit in vivo
testing. Strategically, we will approach this problem using newly developed high-throughput biochemical and
yeast genetic screening tools (Aim 1) that are expected to identify mutations that alter chromatin stability and/or
that affect the activity of trans-acting factors that operate on the chromatin polymer. Validation of the ‘hits’ from
the screening studies will form the core of Aims 2 & 3 where we will combine the use of chemically-defined
chromatin templates with biochemical, proteomic and genomic approaches to develop a mechanistic
understanding of how select mutations impact chromatin state. In particular, we will study how breakdown in
nucleosome symmetry, as a result of sub-stoichiometric incorporation of mutant histones, affects key processes
such as chromatin remodeling and transcription. We imagine that many of the technologies developed in the
context of this work will have broad utility in the epigenetics field generally. Ultimately, the biochemical knowledge
base generated in the course of this program will motivate future therapeutic efforts for treating cancers
associated with oncohistone mutants.

## Key facts

- **NIH application ID:** 10024845
- **Project number:** 2P01CA196539-06
- **Recipient organization:** ROCKEFELLER UNIVERSITY
- **Principal Investigator:** Tom Muir
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $270,959
- **Award type:** 2
- **Project period:** 2015-09-09 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10024845

## Citation

> US National Institutes of Health, RePORTER application 10024845, Project 3: Mechanisms of Methyltransferase Dysregulation by Oncohistones (2P01CA196539-06). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10024845. Licensed CC0.

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