# ATP-Dependent Chromatin Remodeling in Human Malignancy

> **NIH NIH R01** · STANFORD UNIVERSITY · 2023 · $387,313

## Abstract

Project Summary
ATP-Dependent Chromatin Remodeling in Cancer
Chromatin and epigenetic regulators have emerged as important contributors to human cancer. The subunits
of the mSWI/SNF or BAF ATP-dependent chromatin remodeling complex are mutated in over 20% of human
cancers. In addition, several other ATP-dependent remodelers make important contributions to the
pathogenesis of specific cancers. These complexes often function as genetically dominant tumor suppressors,
however the BAF complex also plays oncogenic roles in synovial sarcoma and squamous cell carcinoma.
Despite their prevalent roles in human cancer their oncogenic mechanism(s) remain unclear and a detailed
molecular understanding, necessary for therapeutic development, has been elusive. One of the most well
documented roles of BAF complexes is their opposition to Polycomb Repressive Complexes (PRC)
complexes. Indeed, BAF subunits were discovered in flies as suppressors of PRC1 mutations. In addition,
inhibition of PRC is therapeutic in some cancers having loss of function mutations in the BAF complex.
However, the mechanisms underlying the opposition between BAF chromatin remodeling complexes and
Polycomb complexes is still unclear. We will obtain a detailed understanding of the physical interaction
between these complexes and explore their oncogenic roles with the goal of identifying potential sites of
therapeutic intervention. One possible mechanism underlying the BAF-PRC opposition is the potential of BAF
complexes to exchange or evict nucleosomes modified by PRC1 and 2. Measured rates of nucleosome
exchange by several techniques and by several groups show that nucleosomes exchange several times per
cell cycle. This observation seems inconsistent with the widely held concept that histone and/or nucleosome
modifications are the basis of epigenetic and phenotypic stability. Another way of stating this is “why do the 32
SNF2-like ATP-dependent remodelers encoded in the mammalian genome not quickly erase all histone
modifications by nucleosome exchange? This conflict would be resolved if nucleosome exchange by ATP-
dependent remodelers was selective to a specific remodeler and a specific nucleosomal modification. Thus,
we are developing two new techniques that will fill this gap in our knowledge by measuring exchange of
specifically modified nucleosomes and attributing them to specific remodelers, including their post translational
or oncogenic modifications. These techniques should allow the understanding of the paradox that rates of
nucleosome exchange appear to be far faster than the rate of change of histone modifications. We will use
these techniques to assign changes in the epigenetic landscape to specific ATP-dependent chromatin
regulators and to understand the stability of epigenetic histone modifications in normal and malignant cells. At
the conclusion of our studies, we hope to have a deeper and more detailed understanding of both the normal
and oncogenic mechanisms related to ...

## Key facts

- **NIH application ID:** 10586587
- **Project number:** 2R01CA163915-11A1
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** Gerald R. Crabtree
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $387,313
- **Award type:** 2
- **Project period:** 2012-07-10 → 2028-02-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10586587

## Citation

> US National Institutes of Health, RePORTER application 10586587, ATP-Dependent Chromatin Remodeling in Human Malignancy (2R01CA163915-11A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10586587. Licensed CC0.

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