# Dissecting the molecular mechanisms of PRC2 dysregulation in cancer

> **NIH NIH K00** · MASSACHUSETTS INSTITUTE OF TECHNOLOGY · 2024 · $100,563

## Abstract

Project Summary/Abstract
The chromatin landscape governs basic cellular functions that are altered in cancer, including
genomic architecture, gene expression, and developmental pathways. Interestingly, epigenetic dysregulation of
chromatin is an emerging hallmark of cancer. These epigenetic changes in turn render cancer cells highly reliant
on the chromatin machinery to maintain their malignant state, thus creating opportunities for therapeutic
intervention by targeting chromatin modifiers. Driven by the desire to understand the basic mechanistic
underpinnings of epigenetic regulation, it is my goal to address pressing questions in molecular biology and
contribute to the advancement of cancer prevention and treatment. Histone post-translational modifications
(PTMs) are central regulators of chromatin processes, and genes encoding chromatin factors are highly mutated
in a range of cancers. This project seeks to understand the role of the Polycomb Repressive Complex 2 (PRC2)
in cancer development. PRC2 is a major epigenetic machinery responsible for the maintenance of
heterochromatin and catalysis of histone H3 lysine 27 methylation.
 The F99 phase of this proposal is focused on investigating the regulation of PRC2 enzymatic activity by
the highly conserved SANT1-like binding (SBD) domain of its EZH2 subunit. Despite the broad understanding
of PRC2 function and regulation, the molecular role of the N-terminal SBD of EZH2 is unknown. The
preliminary data reveals novel mechanistic insight about this domain in the catalysis of H3K27 methylation.
Surprisingly, partial deletion of the SBD domain in EZH2 (SBD-EZH2) leads to a global loss of repressive
H3K27me2 and H3K27me3, phenocopying the complete loss of EZH2 at the epigenomic level. In the
remainder of the dissertation work, my main research efforts will be directed toward delineating the regulatory
significance of the EZH2-SBD domain in the allosteric activation of PRC2 enzymatic activity, as well as
determining a potential inhibitory mechanism for lymphoma patients harboring EZH2 gain-of-function mutations.
 The K00 phase of this project will be focused on studying the role of PRC2 loss in the development of
the highly aggressive malignant peripheral nerve sheath tumors (MPNSTs). Interestingly, the loss of PRC2
components is involved in the malignant formation of sporadic and radiotherapy-associated MPNSTs. Thus, to
further understand the molecular mechanisms of these tumors, I plan to expand my technical expertise to include
high-throughput genetic screening, single-cell epigenomic and transcriptomic techniques, computational
approaches, development of preclinical cancer models, and sequencing analysis of human tumor data. These
new approaches, coupled with my already strong background in molecular biology, microscopy, and
biochemistry, will allow me to address the most pressing and challenging issues in epigenetic regulation and
cancer biology today. This award will allow to pursue the above que...

## Key facts

- **NIH application ID:** 10863891
- **Project number:** 5K00CA253687-04
- **Recipient organization:** MASSACHUSETTS INSTITUTE OF TECHNOLOGY
- **Principal Investigator:** Agata Ewa Patriotis
- **Activity code:** K00 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $100,563
- **Award type:** 5
- **Project period:** 2023-06-01 → 2027-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10863891

## Citation

> US National Institutes of Health, RePORTER application 10863891, Dissecting the molecular mechanisms of PRC2 dysregulation in cancer (5K00CA253687-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10863891. Licensed CC0.

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