# Characterizing the RNA-mediated recruitment of histone deacetylases to chromatin

> **NIH NIH F30** · CALIFORNIA INSTITUTE OF TECHNOLOGY · 2024 · $53,974

## Abstract

PROJECT SUMMARY
Global histone deacetylation is linked to many types of cancer and is controlled by histone deacetylases
(HDACs). Although HDAC inhibitors are widely used in cancer treatment, their activity does not target specific
HDAC isoforms nor specific genes and therefore results in significant side effects for patients. Thus, there is a
pressing need to target HDAC activity in a highly precise, gene-specific manner to develop safer and more
effective treatments. The overall objective of this proposal is to understand how HDACs are recruited to specific
genome regions. Because HDACs do not possess intrinsic DNA binding activity, they are thought to be recruited
to chromatin through interactions with DNA binding proteins, though this mechanism has not been fully explored.
Recently, our lab and others identified that the SHARP RNA-binding protein directly interacts with the Xist long
noncoding RNA (lncRNA) to specifically recruit HDAC3 to the future inactive X chromosome (Xi). In this way, the
Xist-SHARP/SMRT/HDAC3 repressive complex deacetylates histones and silences gene expression on the Xi.
Our lab has also demonstrated that SHARP localizes to many nuclear sites (beyond the Xi) in an RNA-dependent
manner, raising the question of which additional RNAs recruit it (along with HDAC3) and to what specific genomic
locations. Notably, nearly all human HDACs associate within multi-protein complexes containing SHARP and
other RNA-binding proteins, suggesting that this mechanism of RNA-guidance may extend beyond SHARP and
Xist.
I hypothesize that HDAC complexes are recruited by RNAs to achieve specificity to their various regulatory
targets throughout the nucleus. First, I will determine which SHARP-RNA interactions are functionally important
by genetically perturbing the SHARP binding sites of candidate RNAs. I will then measure effects on gene
expression and if HDAC3 activity is required for these effects (Aim 1). Second, I will comprehensively identify
RNA-binding proteins associated with other cancer-associated HDACs and define their in vivo RNA binding sites.
I will then determine which protein-bound candidate RNAs from this screen are regulated in an HDAC-dependent
manner (Aim 2). The proposed research has the potential to transform our understanding of RNAs and RNA-
binding proteins as central regulators in organizing chromatin modifications by HDACs in both normal and
cancerous cell states.

## Key facts

- **NIH application ID:** 10852840
- **Project number:** 5F30CA278005-02
- **Recipient organization:** CALIFORNIA INSTITUTE OF TECHNOLOGY
- **Principal Investigator:** James Kang Guo
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $53,974
- **Award type:** 5
- **Project period:** 2023-06-01 → 2028-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10852840

## Citation

> US National Institutes of Health, RePORTER application 10852840, Characterizing the RNA-mediated recruitment of histone deacetylases to chromatin (5F30CA278005-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10852840. Licensed CC0.

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