# Remodeling and Spacing Factor 1 in Histone H2A Ubiquitination-Mediated Gene Silencing

> **NIH NIH R01** · VIRGINIA COMMONWEALTH UNIVERSITY · 2020 · $108,981

## Abstract

Posttranslational modifications of histones play important roles in the regulation of chromatin structure and
function. Histone H2A ubiquitination is a predominant modification important for a variety of cellular processes.
We have previously discovered that Polycomb Repressive Complex 1 (PRC1), a fundamental developmental
regulator, acts as a ubiquitin ligase for H2AK119 ubiquitination (H2AK119ub). This study links H2AK119ub to
PRC1-mediated gene silencing of key developmental genes and the essential roles of PRC1 in cell identity,
tumorigenesis, and genomic imprinting. Several proteins have been shown to bind H2AK119ub; however, how
this modification elicits downstream gene silencing events remains largely obscure. We recently identified
Remodeling and Spacing Factor 1 (RSF1) as a novel H2AK119ub-binding protein, providing a gateway to dissect
the mechanism of action of H2AK119ub. We discovered that RSF1 binds H2AK119ub through a previously
uncharacterized region designated as the ubiquitinated H2A binding (UAB) motif, and that RSF1 is required both
for silencing of H2AK119ub target genes and for maintaining the normal H2AK119ub nucleosome pattern at
promoter regions. We further demonstrated that, during Xenopus early embryonic development, RSF1 regulates
mesodermal cell specification and gastrulation in a fashion similar to Ring1, a Xenopus PRC1 subunit mediating
H2AK119ub. Although these studies reveal that RSF1, as a H2AK119ub-binding protein, is required for
H2AK119ub target gene repression, it remains to be established that reading the H2AK119ub mark is the
mechanism by which RSF1 represses gene expression. Here, we propose a series of structural, in vitro, and in
vivo studies to delineate the mechanism of action of RSF1 in H2AK119ub function. We hypothesize that RSF1
is a key reader of H2AK119 ubiquitination that mediates its roles in gene silencing, chromatin
remodeling, and development. We propose to address three questions critical to this hypothesis: 1) how does
RSF1 specifically recognize H2AK119ub nucleosomes? 2) how does RSF1 modulate the organization of
H2AK119ub chromatin? and 3) what is the significance of RSF1 in H2AK119ub-regulated physiological
processes? Given the fundamental roles of PRC1 and RSF1 in cell fate determination during normal
development and the extensive involvement of PRC1 and RSF1 in cancer development, these studies will
significantly advance our understanding of the epigenetic mechanisms controlling normal development as well
as pathogenic processes.

## Key facts

- **NIH application ID:** 10643591
- **Project number:** 7R01GM130696-03
- **Recipient organization:** VIRGINIA COMMONWEALTH UNIVERSITY
- **Principal Investigator:** HENGBIN WANG
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $108,981
- **Award type:** 7
- **Project period:** 2019-09-20 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10643591

## Citation

> US National Institutes of Health, RePORTER application 10643591, Remodeling and Spacing Factor 1 in Histone H2A Ubiquitination-Mediated Gene Silencing (7R01GM130696-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10643591. Licensed CC0.

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