# Role of Histone and Histone-like Mutations in the Oncogenesis of Human Cancers

> **NIH NIH P01** · ROCKEFELLER UNIVERSITY · 2022 · $1,670,815

## Abstract

Project Summary (Overall)
The chromatin landscape impacts fundamental cellular processes including gene expression, DNA damage
repair, and cell fate and differentiation, all of which are extensively dysregulated in cancer. The collective number
of oncogenic mutations in chromatin regulators has led to the emerging view of driver mutations underlying
cancer epigenomes. In keeping with theme, over the past several years our current collaborative program
members have been critical to the discovery and characterization of ‘classical’ oncohistone mutations in the
histone H3.3 N-terminal tail. These mutations globally alter chromatin by inhibiting the activity of chromatin
modifying enzymes. While much progress has been made to understand these effects, important questions
remain including the nature of the dysregulation of chromatin modifying enzymes by these mutations and how
these mutations lead to cancer. In addition, Program members have recently identified an expanded number of
cancer-associated somatic histone mutations that occur in as many as 4 % of human cancers and involve both
globular and tail domains of all four core histones. These findings generate additional important questions such
as if the newly observed histone mutations have functional effects on chromatin and through what mechanisms
they rely on. Given that some of the most prevalent mutations are in the globular domains of histones, we
hypothesize that these mutations affect nucleosome structure and/or integrity. Lastly, we and others have also
identified a novel function of the EZHIP protein, which is overexpressed in posterior fossa A ependymomas, and
acts as an oncohistone mimic to directly inhibit the Polycomb Repressive Complex 2 (PRC2) function. The single
goal of our Program is to illuminate the molecular mechanisms underlying classical and novel “oncohistone”
mutations and oncohistone mimics to advance the diagnosis and exploration of therapeutic avenues for the
cancers. Specifically, we will: i) develop and employ novel patient sample-, cell culture- and animal model-based
systems to recapitulate oncohistone-associated cancers and investigate the underlying pathogenic mechanisms;
ii) evaluate the activity of a comprehensive set of novel cancer-associated histone mutations using a
multidisciplinary approach that includes genetics (barcoded oncohistone libraries, mouse models, barcoded-cell
lines), epigenetics (ChIP-seq, ATAC-seq, DNA-methylation profiling), transcriptomics (RNA-seq), and chemical
biology (“designer chromatin”, small molecule inhibitors); iii) define the mechanisms by which oncohistones, and
oncohistone-mimics, dysregulate the Polycomb Repressive Complexes (PRC1 and PRC2) activity to promote
gliomas and bone tumors; and iv) identify which of novel histone mutations perturb chromatin states (and by
what mechanisms) to subsequently cause cellular phenotype using newly developed high-throughput
biochemical and yeast genetic screening tools. These studies wil...

## Key facts

- **NIH application ID:** 10489397
- **Project number:** 5P01CA196539-08
- **Recipient organization:** ROCKEFELLER UNIVERSITY
- **Principal Investigator:** Tom Muir
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $1,670,815
- **Award type:** 5
- **Project period:** 2015-09-09 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10489397

## Citation

> US National Institutes of Health, RePORTER application 10489397, Role of Histone and Histone-like Mutations in the Oncogenesis of Human Cancers (5P01CA196539-08). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10489397. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*