# Regulation of gene expression by HDAC3

> **NIH NIH R01** · MAYO CLINIC ROCHESTER · 2020 · $537,471

## Abstract

Abstract
Differentiation of multi-potent progenitors into T cells requires an intricate interplay between transcriptional
regulators as thymocytes proceed through each stage of development. Gene expression is controlled through
regulating transcriptional activation and chromatin accessibility. Histone deacetylases (HDACs) limit chromatin
accessibility and transcription. DP thymocytes co-express all 18 HDAC family members, but whether co-
expressed HDACs have specific or overlapping functions is not well understood. Our work has demonstrated
that HDAC3 has a unique role in T cell development, which is not compensated for by any other co-expressed
HDAC family member. HDAC3 is required for DP survival and positive selection. CD2-icre HDAC3 cKO mice
have decreased numbers of DP thymocytes with a severe block in thymocyte positive selection resulting in few
SP thymocytes produced. Mechanistically, the block in positive selection in CD2-icre HDAC3 cKO mice is due
to a failure to downregulate a single gene, RORγt. Similarly, HDAC3 is required to suppress expression of the
purinergic receptor P2RX7 in DP thymocytes, and increased P2RX7 expression contributes to the defect in DP
survival in CD2-icre HDAC3 cKO mice. HDAC3 is required to inhibit premature expression of genes that direct
commitment to the CD8 lineage. Changes in gene expression and H3K27 or H3K9 histone acetylation were
restricted, rather than global, in HDAC3-deficient DP thymocytes. Genes whose expression is normally
restricted to other (non-T) hematopoietic lineages remain off in the absence of HDAC3, and housekeeping
genes are expressed at similar levels between WT and HDAC3-deficient DP thymocytes. Therefore, HDAC3
is not a generic or general modifier of gene regulation. Instead, HDAC3 has specific functions in a small set of
genes that are critical for DP survival, positive selection and CD4/CD8 lineage choice. The focus of this
proposal is to define how HDAC3 is recruited to those genes in DP thymocytes, the alterations in chromatin
which accompany HDAC3 recruitment and the binding partners critical for HDAC3 function.

## Key facts

- **NIH application ID:** 9993743
- **Project number:** 1R01AI150100-01A1
- **Recipient organization:** MAYO CLINIC ROCHESTER
- **Principal Investigator:** Virginia Smith Shapiro
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $537,471
- **Award type:** 1
- **Project period:** 2020-08-01 → 2024-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9993743

## Citation

> US National Institutes of Health, RePORTER application 9993743, Regulation of gene expression by HDAC3 (1R01AI150100-01A1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9993743. Licensed CC0.

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