# Mechanism of heterochromatin assembly and oncogenic histone mutations

> **NIH NIH R35** · COLUMBIA UNIV NEW YORK MORNINGSIDE · 2021 · $394,836

## Abstract

Project Summary
Covalent modifications of histones, such as acetylation, methylation, phosphorylation, and ubiquitylation, are
essential regulators of chromatin structure and function. Defects in the regulation of these modifications have
causal roles in numerous developmental disorders and diseases. However, the mechanisms that target
histone-modifying enzymes to specific genomic locations and regulate their enzymatic activities are not well
understood. Our long-term goal is to understand how diverse histone modification activities are coordinated to
initiate and maintain different epigenetic states using heterochromatin assembly and oncogenic histone
mutations as experimental models.
Heterochromatin preferentially assembles at repetitive DNA elements and it is essential for the regulation of
gene expression and the maintenance of genome integrity. Formation of heterochromatin is critically
dependent on the methylation of H3 lysine 9 (H3K9), and it is generally assumed that precise targeting of
histone H3K9 methyltransferases confines heterochromatin to specific genomic regions. However, our recent
studies demonstrate that in fission yeast the targeting of H3K9 methyltransferases Clr4 is not very precise, and
cells rely critically on negatively regulators, such as the Mst2 histone acetyltransferase and the Epe1 histone
demethylase, to remove heterochromatin at inappropriate locations. We will therefore analyze the molecular
functions of Mst2 and Epe1 in heterochromatin formation, and examine how their activities change in response
to environmental signals to regulate heterochromatin dynamics.
Recent high throughput sequencing analyses discovered high incidences of somatic histone lysine-to-
methionine (K-to-M) mutations in multiple cancers. These mutations block the methylation of wild type histones.
However, the molecular details by which these mutations function are poorly understood and are highly
controversial. We have established fission yeast models in which the introduction of H3K9M or H3K36M
transgenes abolished the methylation of corresponding lysines on wild type histones, similar to the effects of
these mutations in mammalian systems. We will examine how these mutations regulate cellular functions and
identify pathways that can be targeted to selectively kill cells containing K-to-M mutations.
The ultimate goal of these studies is a complete understanding of how histone methylations are regulated and
how their mutations and dysregulation contribute to human diseases.

## Key facts

- **NIH application ID:** 10219813
- **Project number:** 5R35GM126910-04
- **Recipient organization:** COLUMBIA UNIV NEW YORK MORNINGSIDE
- **Principal Investigator:** Songtao Jia
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $394,836
- **Award type:** 5
- **Project period:** 2018-08-07 → 2023-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10219813

## Citation

> US National Institutes of Health, RePORTER application 10219813, Mechanism of heterochromatin assembly and oncogenic histone mutations (5R35GM126910-04). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10219813. Licensed CC0.

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