The structure of chromatin is tightly regulated by the well choreographed actions of multiple elements. Disruption of the normal pattern of chromatin often leads to mis-regulation of gene expression, a common feature of cancer and other human diseases. Therefore, it is important to understand the detailed mechanism regulating chromatin dynamics. The long-term objective of this proposal is to understand how chromatin- related complexes help the transcription machinery overcome the nucleosomal barriers while still maintaining genome integrity. Recently, we and others discovered a novel signaling pathway through which RNA polymerase II (Pol II) maintains chromatin integrity while transcribing through nucleosomal templates. A histone methyltransferase Set2 binds the phosphorylated CTD of elongating Pol II and co-transcriptionally methylates histone H3K36, which is then recognized by a histone deacetylase complex, Rpd3S. Once targeted, Rpd3S deacetylates transcribed regions to preserve the accuracy of transcription initiation, thus restricting transcription to bonafide promoters but not cryptic transcription start sites. This proposal is intended to dissect the detailed mechanisms driving this crucial pathway via three specific aims. (1) Analysis of Rpd3S binding to K36 methylated nucleosomes and its implication in transcription elongation. We will test how multiple domains within Rpd3S coordinate to achieve synergistic binding. (2) Dissecting the molecular mechanism by which Pol II exploits K36 methylation as a marker for short term transcription memory. We will examine if elongating Pol II can control the directionality of relevant histone modifications around the transcription fork. (3) Identification of the temporal control mechanism of K36 methylation during transcription elongation. We will explore the roles of histone demethylases and the signals for removal of this reversible histone modification. Importantly, human Set2 has been shown to interact with Huntingtin, the Huntington disease protein;and the treatment of histone deacetylase inhibitors can arrest neurodegeneration in a model system. Therefore, our understanding on the Set2- Rpd3S pathway may also help design potential therapeutic agents to treat neurodegenerative diseases.

Public Health Relevance

The results from these studies are expected to advance our understanding of histone code recognition. Many diseases such as cancer and neurodegeneration have been linked to defects in histone modification or the targeting of proteins to modified histones. Thus, our work will provide important potential targets for drugs that treat a variety of human diseases.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
Project #
Application #
Study Section
Molecular Genetics B Study Section (MGB)
Program Officer
Carter, Anthony D
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Texas Sw Medical Center Dallas
Schools of Medicine
United States
Zip Code
Schibler, Andria; Koutelou, Evangelia; Tomida, Junya et al. (2016) Histone H3K4 methylation regulates deactivation of the spindle assembly checkpoint through direct binding of Mad2. Genes Dev 30:1187-97
McDaniel, Stephen L; Fligor, Jennifer E; Ruan, Chun et al. (2016) Combinatorial Histone Readout by the Dual Plant Homeodomain (PHD) Fingers of Rco1 Mediates Rpd3S Chromatin Recruitment and the Maintenance of Transcriptional Fidelity. J Biol Chem 291:14796-802
Ruan, Chun; Cui, Haochen; Lee, Chul-Hwan et al. (2016) Homodimeric PHD Domain-containing Rco1 Subunit Constitutes a Critical Interaction Hub within the Rpd3S Histone Deacetylase Complex. J Biol Chem 291:5428-38
Mayfield, Joshua E; Fan, Shuang; Wei, Shuo et al. (2015) Chemical Tools To Decipher Regulation of Phosphatases by Proline Isomerization on Eukaryotic RNA Polymerase II. ACS Chem Biol 10:2405-14
Wang, Yi; Niu, Yanling; Li, Bing (2015) Balancing acts of SRI and an auto-inhibitory domain specify Set2 function at transcribed chromatin. Nucleic Acids Res 43:4881-92
Ruan, Chun; Lee, Chul-Hwan; Cui, Haochen et al. (2015) Nucleosome contact triggers conformational changes of Rpd3S driving high-affinity H3K36me nucleosome engagement. Cell Rep 10:204-15
Ginsburg, Daniel S; Anlembom, Timi Elvuchio; Wang, Jianing et al. (2014) NuA4 links methylation of histone H3 lysines 4 and 36 to acetylation of histones H4 and H3. J Biol Chem 289:32656-70
Wen, Hong; Li, Yuanyuan; Xi, Yuanxin et al. (2014) ZMYND11 links histone H3.3K36me3 to transcription elongation and tumour suppression. Nature 508:263-8
Lee, Chul-Hwan; Wu, Jun; Li, Bing (2013) Chromatin remodelers fine-tune H3K36me-directed deacetylation of neighbor nucleosomes by Rpd3S. Mol Cell 52:255-63
Yun, Miyong; Ruan, Chun; Huh, Jae-Wan et al. (2012) Reconstitution of modified chromatin templates for in vitro functional assays. Methods Mol Biol 833:237-53

Showing the most recent 10 out of 15 publications