Integrator is a multi-protein complex stably associated with the C-terminal domain (CTD) of RNA polymerase II (RNAPII). Integrator contains a catalytic RNA endonuclease subunit (INTS11) with high degree of homology to cleavage and polyadenylation specificity factor 73 (CPSF73), the enzyme responsible for cleavage and termination of messenger RNA (mRNA) genes. We showed that Integrator occupies the small nuclear RNA genes (snRNA) and that its catalytic activity was required for the 3'-end processing of these non- polyadenylated transcripts. We have expanded our functional studies during the course of this grant funding to uncover a role for Integrator at protein-coding genes and distal enhancers. In the proposed studies we intend to illuminate the molecular mechanism underlying Integrator function at enhancers and their respective protein-coding promoters through the following specific aims:
Aim1) We will investigate the molecular mechanisms by which Integrator regulates transcriptional elongation (RNAPII pause release) at protein-coding genes.
Aim 2) We will elucidate the role of Integrator in enhancer RNA biogenesis and enhancer function.
Aim 3) We will address the physical and functional association of Integrator and different phosphorylation states of the CTD in regulation of transcriptional activation.

Public Health Relevance

Enhancers and enhancer RNAs (eRNAs) regulate tissue and temporal-specific gene expression critical for normal development and disease progression. We have discovered that Integrator, an RNA polymerase II associated complex, regulates messenger RNAs (mRNAs) as well as eRNAs. Our studies on Integrator will provide fundamental insight into regulation of gene expression, which will be the basis for development of rational therapies against transcriptional defects in disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM078455-07
Application #
9199218
Study Section
Molecular Genetics A Study Section (MGA)
Program Officer
Sledjeski, Darren D
Project Start
2010-08-01
Project End
2019-12-31
Budget Start
2017-01-01
Budget End
2017-12-31
Support Year
7
Fiscal Year
2017
Total Cost
Indirect Cost
Name
University of Miami School of Medicine
Department
Genetics
Type
Schools of Medicine
DUNS #
052780918
City
Coral Gables
State
FL
Country
United States
Zip Code
33146
Bose, Daniel A; Donahue, Greg; Reinberg, Danny et al. (2017) RNA Binding to CBP Stimulates Histone Acetylation and Transcription. Cell 168:135-149.e22
Chen, Fei Xavier; Xie, Peng; Collings, Clayton K et al. (2017) PAF1 regulation of promoter-proximal pause release via enhancer activation. Science 357:1294-1298
Yue, Jingyin; Lai, Fan; Beckedorff, Felipe et al. (2017) Integrator orchestrates RAS/ERK1/2 signaling transcriptional programs. Genes Dev 31:1809-1820
Witt, A E; Lee, C-W; Lee, T I et al. (2017) Identification of a cancer stem cell-specific function for the histone deacetylases, HDAC1 and HDAC7, in breast and ovarian cancer. Oncogene 36:1707-1720
Li, Na; Li, Yuanyuan; Lv, Jie et al. (2016) ZMYND8 Reads the Dual Histone Mark H3K4me1-H3K14ac to Antagonize the Expression of Metastasis-Linked Genes. Mol Cell 63:470-84
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Yang, Mei; Liang, Chen; Swaminathan, Kunchithapadam et al. (2016) A C9ORF72/SMCR8-containing complex regulates ULK1 and plays a dual role in autophagy. Sci Adv 2:e1601167
Kim, Tae-Kyung; Shiekhattar, Ramin (2015) Architectural and Functional Commonalities between Enhancers and Promoters. Cell 162:948-59
Lai, Fan; Gardini, Alessandro; Zhang, Anda et al. (2015) Integrator mediates the biogenesis of enhancer RNAs. Nature 525:399-403
Gardini, Alessandro; Shiekhattar, Ramin (2015) The many faces of long noncoding RNAs. FEBS J 282:1647-57

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