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Transcriptional regulatory networks in living cells

Award Number: R01GM123511
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: 05/02/2003
PERIOD OF PERFORMANCE END DATE: 06/30/2022

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Transcriptional regulatory networks in living cells - R01 GM123511 Richard Young Proper control of gene expression programs is fundamental to cellular health and its dysregulation has been implicated in many human diseases. The gene expression programs of mammalian cells are regulated by diverse transcription factors and cofactors, which occupy specific genomic loci and cause RNA polymerase II to transcribe specific genes. When regulated properly, this transcriptional circuitry produces healthy cells, but many inherited and infectious diseases cause cells to have dysregulated gene expression programs. While pursuing the original aims of our project, we discovered that components of the transcription apparatus form a liquid-like condensate that compartmentalizes and concentrates these transcriptional molecules at super-enhancers and their associated genes (Cell 2018, PMC6295254, Science, 2018, PMC6092193; Nature 2019, PMC6706314). This new model has led us to fundamental new insights; for example, the heretofore mysterious activation domains of transcription factors, whose intrinsically disordered domains do not form stable structures amenable to crystallography, are now understood to activate genes through their ability to form dynamic condensates with coactivators and RNA polymerase II. Gaps in our knowledge of the factors that contribute to transcriptional condensates now limit our understanding of the mechanisms by which these factors contribute to specific cell states in health and disease. The new condensate model for transcriptional control, and recent evidence that SARS-CoV-2 modulates host cell gene expression by sequestering host components that normally occur in nuclear condensates, compels us to pursue simultaneously both our original goal of improving our understanding of human gene control and a new goal of deciphering how SARS-CoV-2 alters normal host cell gene expression. To accomplish this goals, the specific aims of the project are: 1) identify and characterize the functions of coactivators in active transcriptional condensates, 2) identify and characterize the functions of corepressors in heterochromatic condensates, and 3) determine how host cell gene expression is manipulated by SARS-CoV-2 accessory proteins, which have been shown to bind and sequester host cell transcriptional coactivators and corepressors. These related studies promise to continue to produce new insights into the control of gene expression programs and should generate new insights into the mechanisms by which SARS-CoV-2 alters these programs, thereby providing clues to mechanisms with potential therapeutic value.


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: 2023 ( Subtotal = $0 )
2023	2020	WHITEHEAD INSTITUTE FOR BIOMEDICAL RESEARCH	455 MAIN ST	CAMBRIDGE	MA	02142	MIDDLESEX	USA	Biomedical Research and Research Training	000	17	1/10/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2020 ( Subtotal = $907,395 )
2020	2020	WHITEHEAD INSTITUTE FOR BIOMEDICAL RESEARCH	455 MAIN ST	CAMBRIDGE	MA	02142	MIDDLESEX	USA	Biomedical Research and Research Training	001	17	6/23/2020	NON-COMPETING CONTINUATION	$907,395
2020	2019	WHITEHEAD INSTITUTE FOR BIOMEDICAL RESEARCH	455 MAIN ST	CAMBRIDGE	MA	02142	MIDDLESEX	USA	Biomedical Research and Research Training	000	16	5/6/2020	NON-COMPETING CONTINUATION	$0
														Subtotal = $907,395

Issue Date FY: 2019 ( Subtotal = $907,395 )
2019	2019	WHITEHEAD INSTITUTE FOR BIOMEDICAL RESEARCH	455 MAIN ST	CAMBRIDGE	MA	02142	MIDDLESEX	USA	Biomedical Research and Research Training	000	16	6/25/2019	NON-COMPETING CONTINUATION	$907,395
														Subtotal = $907,395

Issue Date FY: 2018 ( Subtotal = $907,442 )
2018	2018	WHITEHEAD INSTITUTE FOR BIOMEDICAL RESEARCH	455 MAIN ST	CAMBRIDGE	MA	02142	MIDDLESEX	USA	Biomedical Research and Research Training	001	15	6/20/2018	NON-COMPETING CONTINUATION	$907,395
2018	2017	WHITEHEAD INSTITUTE FOR BIOMEDICAL RESEARCH	455 MAIN ST	CAMBRIDGE	MA	02142	MIDDLESEX	USA	Biomedical Research and Research Training	000	14	6/1/2018	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$47
														Subtotal = $907,442

Issue Date FY: 2017 ( Subtotal = $907,395 )
2017	2017	WHITEHEAD INSTITUTE FOR BIO-MEDICAL RESEARCH	9 CAMBRIDGE CTR	CAMBRIDGE	MA	02142	MIDDLESEX	USA	Biomedical Research and Research Training	000	14	5/31/2017	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$907,395
														Subtotal = $907,395

Grand Total All Awards = $3,629,627

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Transcriptional regulatory networks in living cells

Award Number: R01GM123511

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: 05/02/2003

PERIOD OF PERFORMANCE END DATE: 06/30/2022

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