# The Positive Roles of Lysine Deacetylase Complexes in Regulating Transcriptional Dynamics (Diversity Supplement)

> **NIH NIH R01** · UNIVERSITY OF ARIZONA · 2022 · $16,282

## Abstract

PROJECT SUMMARY
Whereas traditional models of transcription cast lysine acetyltransferases (KATs, also known as HATs) as tran-
scriptional coactivators and lysine deacetylases (KDACs, also known as HDACs) as corepressors, an abun-
dance of evidence demonstrates that KDACs can facilitate transcription in a gene-dependent fashion. However,
the mechanisms underlying their transcription-promoting functions are poorly understood. The long-term goal of
our work is to define mechanisms by which KDACs, KATs, and acetylation regulate signaling-modulated tran-
scription. The proposed study utilizes glucocorticoid signaling as a model system. Published studies from the lab
demonstrate that KDACs are required not only for glucocorticoid-mediated transcriptional repression but also for
transcriptional activation of target genes. Preliminary studies show that KDAC1 is required for GR-activated
transcription by multiple mechanisms, depending on the target gene, acting either upstream or downstream of
RNA polymerase II (RNA Pol II) recruitment to the transcription start site (TSS). The next logical step is to identify
the KDAC1 complexes involved and investigate their roles in glucocorticoid receptor (GR)-activated transcription.
The objective of the parent grant (R01GM139829) is to define the roles of KDACs in the dynamics of the tran-
scriptional cycle at glucocorticoid receptor (GR)-activated genes. The objective of the research plan described
in this diversity supplement is to investigate the impact of KDAC activity on the dynamics of RNA polymerase II
association with GR-activated genes. This hypothesis will be tested experimentally through three specific aims.
In the first specific aim, the impact of Class I KDACs on the kinetics of transcriptional bursting at GR-activated
genes will be measured to identify GR-activated genes that are regulated by KDAC activity upstream or down-
stream of transcriptional initiation, working from the hypothesis that the mechanism by which KDACs facilitate
transcription is gene-specific. In the second specific aim, the impact of KDAC activity on RNA pol II distribution
and the pattern of nascent transcription at enhancers, promoters, and gene bodies of GR-activated genes will
be determined genome-wide. The working hypothesis is that KDAC activity regulates transcription and RNA pol
II dynamics at distinct gene regions in a gene-specific fashion. In the third specific aim the dynamics of histone
acetylation and RNA pol II will be investigated at a GR-activated gene at which transcription can be visualized
in live cells. This will be performed using nanobodies to detect histone acetylation and RNA pol II in live cells.
This work will generate novel mechanistic knowledge of the transcriptional functions of KDACs that is relevant
to basic understanding of cellular processes as well as treatment of disease through modulation of the epige-
nome. Importantly, in the process of doing this research the graduate student who will be su...

## Key facts

- **NIH application ID:** 10612509
- **Project number:** 3R01GM139829-02S1
- **Recipient organization:** UNIVERSITY OF ARIZONA
- **Principal Investigator:** Catharine Lynn Smith
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $16,282
- **Award type:** 3
- **Project period:** 2020-12-01 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10612509

## Citation

> US National Institutes of Health, RePORTER application 10612509, The Positive Roles of Lysine Deacetylase Complexes in Regulating Transcriptional Dynamics (Diversity Supplement) (3R01GM139829-02S1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10612509. Licensed CC0.

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