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Mechanisms of RNA polymerase II transcription regulation

Award Number: R35GM139550
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 01/01/2021
PERIOD OF PERFORMANCE END DATE: 12/31/2030

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Mechanisms of RNA polymerase II transcription regulation - SUMMARY Our research program combines biochemical reconstitution with powerful cell-based assays, with a goal of obtaining fundamental mechanistic insights about human RNA polymerase II (RNAPII) function and its regulation. RNAPII transcribes all protein-coding and many non-coding RNAs in the human genome. RNAPII transcription initiation is regulated by the 4.0 MDa Pre-Initiation Complex (PIC), which contains TFIIA, IIB, IID, IIE, IIF, IIH, RNAPII, and Mediator. Together with sequence-specific, DNA-binding transcription factors (TFs), the PIC directs the timing, location, and direction of RNAPII transcription, genome-wide. How TFs and the PIC work together during different stages of RNAPII transcription (e.g. initiation, promoter-proximal pausing, pause release or termination) remain incompletely understood; moreover, recent insights have transformed existing models for how gene expression is regulated. For instance, i) RNAPII transcription occurs in short bursts of activity, often generating multiple transcripts from a single promoter, ii) liquid phase separated condensates have been widely implicated to regulate RNAPII activity in cells, and iii) enhancer RNA (eRNA) transcription and transient enhancer-promoter interactions appear to drive lineage-specific, signal-specific, and pathogenic gene expression programs. These new mechanistic models cannot be rigorously tested using only cell-based methods, because of limited spatial and temporal resolution and because of the enormous complexity of cellular systems. For instance, the identity and concentration of the proteins, nucleic acids, and biochemicals present at any given gene in a population of cells cannot possibly be defined. In the next 5 years, we propose to leverage our unique expertise in biochemical reconstitution of human RNAPII transcription with cutting-edge cellular methods to address the following high-impact questions: 1) How is RNAPII activity controlled at gene promoters? We will systematically test how RNAPII bursting and re-initiation, promoter-proximal pausing, and termination is controlled by the transcriptional kinases CDK7 (TFIIH subunit), CDK8 (Mediator-associated kinase), and CDK9 (P-TEFb kinase), as well as TFIIS and the Integrator complex. Each of these factors are genome-wide regulators of RNAPII function. 2) condensates super-activate RNAPII transcription? Using our innovative RIFT assay Can molecular that combines smTIRF with biochemical reconstitution, we will directly image condensates and RNAPII transcription at single promoters for the first time, to define how (or whether) condensates control RNAPII function. 3) How do enhancers activate RNAPII? Using purified factors, we will dissect the mechanistic requirements for bidirectional eRNA transcription, and test mechanistic models of enhancer function through direct smTIRF visualization of enhancer-promoter activation in real time. An equally important aspect of our research plan is to rigorously test the models that emerge from systematic in vitro assays through targeted, cell-based assays, which will implement genome-editing, chemical biology, transcriptomics, and other approaches.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $617,496 )
2026	2026	THE REGENTS OF THE UNIVERSITY OF COLORADO	3100 MARINE ST	BOULDER	CO	80309	BOULDER	USA	Biomedical Research and Research Training	002	6	2/24/2026	COMPETING CONTINUATION	$617,496
2026	2025	THE REGENTS OF THE UNIVERSITY OF COLORADO	3100 MARINE ST	BOULDER	CO	80303	BOULDER	USA	Biomedical Research and Research Training	000	5	10/20/2025	NON-COMPETING CONTINUATION	$0
2026	2025	THE REGENTS OF THE UNIVERSITY OF COLORADO	3100 MARINE ST	BOULDER	CO	80309	BOULDER	USA	Biomedical Research and Research Training	001	5	2/23/2026	NON-COMPETING CONTINUATION	$0
														Subtotal = $617,496

Issue Date FY: 2025 ( Subtotal = $633,029 )
2025	2025	THE REGENTS OF THE UNIVERSITY OF COLORADO	3100 MARINE ST	BOULDER	CO	80309	BOULDER	USA	Biomedical Research and Research Training	001	5	12/9/2024	NON-COMPETING CONTINUATION	$569,726
2025	2025	THE REGENTS OF THE UNIVERSITY OF COLORADO	3100 MARINE ST	BOULDER	CO	80309	BOULDER	USA	Biomedical Research and Research Training	002	5	8/13/2025	NON-COMPETING CONTINUATION	$63,303
2025	2024	THE REGENTS OF THE UNIVERSITY OF COLORADO	3100 MARINE ST	BOULDER	CO	80309	BOULDER	USA	Biomedical Research and Research Training	000	4	11/4/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $633,029

Issue Date FY: 2024 ( Subtotal = $633,029 )
2024	2024	THE REGENTS OF THE UNIVERSITY OF COLORADO	3100 MARINE ST	BOULDER	CO	80309	BOULDER	USA	Biomedical Research and Research Training	000	4	12/14/2023	NON-COMPETING CONTINUATION	$569,726
2024	2024	THE REGENTS OF THE UNIVERSITY OF COLORADO	3100 MARINE ST	BOULDER	CO	80309	BOULDER	USA	Biomedical Research and Research Training	001	4	6/25/2024	NON-COMPETING CONTINUATION	$63,303
														Subtotal = $633,029

Issue Date FY: 2023 ( Subtotal = $633,029 )
2023	2023	REGENTS OF THE UNIVERSITY OF COLORADO, THE	3100 MARINE ST STE 481 572 UCB	BOULDER	CO	80309	BOULDER	USA	Biomedical Research and Research Training	001	3	4/14/2023	NON-COMPETING CONTINUATION	$63,303
2023	2023	REGENTS OF THE UNIVERSITY OF COLORADO, THE	3100 MARINE ST STE 481 572 UCB	BOULDER	CO	80309	BOULDER	USA	Biomedical Research and Research Training	000	3	1/5/2023	NON-COMPETING CONTINUATION	$569,726
														Subtotal = $633,029

Issue Date FY: 2022 ( Subtotal = $633,029 )
2022	2022	REGENTS OF THE UNIVERSITY OF COLORADO, THE	3100 MARINE ST STE 481 572 UCB	BOULDER	CO	80309	BOULDER	USA	Biomedical Research and Research Training	000	2	12/8/2021	NON-COMPETING CONTINUATION	$569,726
2022	2022	REGENTS OF THE UNIVERSITY OF COLORADO, THE	3100 MARINE ST STE 481 572 UCB	BOULDER	CO	80309	BOULDER	USA	Biomedical Research and Research Training	001	2	7/14/2022	NON-COMPETING CONTINUATION	$63,303
														Subtotal = $633,029

Issue Date FY: 2021 ( Subtotal = $682,233 )
2021	2021	REGENTS OF THE UNIVERSITY OF COLORADO, THE	3100 MARINE ST STE 481 572 UCB	BOULDER	CO	80309	BOULDER	USA	Biomedical Research and Research Training	001	1	8/10/2021	SUPPLEMENT FOR EXPANSION	$49,204
2021	2021	REGENTS OF THE UNIVERSITY OF COLORADO, THE	3100 MARINE ST STE 481 572 UCB	BOULDER	CO	80309	BOULDER	USA	Biomedical Research and Research Training	000	1	12/24/2020	NEW	$633,029
														Subtotal = $682,233

Grand Total All Awards = $3,831,845

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Mechanisms of RNA polymerase II transcription regulation

Award Number: R35GM139550

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 01/01/2021

PERIOD OF PERFORMANCE END DATE: 12/31/2030

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