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)
Type
Research Project (R01)
Project #
5R01GM078455-07
Application #
9199218
Study Section
Molecular Genetics A Study Section (MGA)
Program Officer
Sledjeski, Darren D
Project Start
Project End
Budget Start
Budget End
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
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Gardini, Alessandro; Baillat, David; Cesaroni, Matteo et al. (2014) Integrator regulates transcriptional initiation and pause release following activation. Mol Cell 56:128-39
Ørom, Ulf Andersson; Shiekhattar, Ramin (2013) Long noncoding RNAs usher in a new era in the biology of enhancers. Cell 154:1190-3

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