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Uncovering the structural underpinnings of function in disordered transcription factor regions

Award Number: R35GM137926
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: 08/01/2020
PERIOD OF PERFORMANCE END DATE: 12/31/2030

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Uncovering the structural underpinnings of function in disordered transcription factor regions - PROJECT SUMMARY Intrinsically disordered protein regions (IDRs) exist in over 70% of the proteins in the human proteome. Despite this abundance, the mechanistic underpinnings of IDR function remain largely unknown. An emerging consensus is that the structural preferences of IDR ensembles - the collection of interconvertible structures in which they exist - can determine their function. In the past five years, my lab has developed new computational and experimental tools to study these ensembles in live cells. Our research showed that structural preferences of IDR ensembles persist inside the cell, but at the same time can be sensitive to changes in sequence or in cellular composition. The functional implications of this sensitivity, however, remain unresolved. My goal for the next five years is to understand how structural preferences in IDR ensembles, and changes to these preferences, affect IDR function. I target three knowledge gaps: 1) When do ensemble structural preferences affect IDR function? 2) Can disease-linked, single-point missense mutations alter ensemble structure and function? 3) Can changes to ensemble structural preferences, caused by a stressed cellular environment, alter IDR function? To bridge these knowledge gaps I will focus on IDRs in transcription factors (tfIDRs). Transcription factors are DNA-binding proteins that initiate gene transcription. Remarkably, the sequence of most of the ~1,500 transcription factors in the human proteome is largely disordered. It is widely accepted that tfIDRs play key roles in recruiting transcriptional machinery, but the mechanism by which they do this, how they may perform other functions, or how functions are modified by changes in their ensemble, remains unknown. Studying the ensemble-function relationships using tfIDRs is ideal because of their clear downstream product - mRNA or gene expression - which provides a quantitative handle on their activity. Experiments targeting these knowledge gaps will focus on using methods previously developed and validated in our lab to correlate tfIDR structural ensemble with transcriptional activity in live cells. Successful completion of these experiments will uncover the impact of mutations and environmental changes on tfIDR function, and reveal fundamental mechanisms in transcription factor function, regulation, and dysfunction. More broadly, our experiments will provide a clear demonstration that the context-dependent structures of IDR ensembles can change their function, turning them into sensors and actuators of the cellular environment.


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 = $411,125 )
2026	2026	SYRACUSE UNIVERSITY	900 S CROUSE AVE	SYRACUSE	NY	13244	ONONDAGA	USA	Biomedical Research and Research Training	000	6	3/11/2026	COMPETING CONTINUATION	$411,125
														Subtotal = $411,125

Issue Date FY: 2025 ( Subtotal = -$371,804 )
2025	2024	UNIVERSITY OF CALIFORNIA, MERCED	5200 N LAKE RD	MERCED	CA	95343	MERCED	USA	Biomedical Research and Research Training	000	5	9/26/2025	NON-COMPETING CONTINUATION	-$371,804
														Subtotal = -$371,804

Issue Date FY: 2024 ( Subtotal = $371,965 )
2024	2024	UNIVERSITY OF CALIFORNIA, MERCED	5200 N LAKE RD	MERCED	CA	95343	MERCED	USA	Biomedical Research and Research Training	000	5	5/16/2024	NON-COMPETING CONTINUATION	$371,965
														Subtotal = $371,965

Issue Date FY: 2023 ( Subtotal = $593,063 )
2023	2023	UNIVERSITY OF CALIFORNIA, MERCED FOUNDATION	5200 N LAKE RD	MERCED	CA	95343	MERCED	USA	Biomedical Research and Research Training	000	4	5/23/2023	NON-COMPETING CONTINUATION	$371,965
2023	2023	UNIVERSITY OF CALIFORNIA, MERCED FOUNDATION	5200 N LAKE RD	MERCED	CA	95343	MERCED	USA	Biomedical Research and Research Training	001	4	7/7/2023	SUPPLEMENT FOR EXPANSION	$221,098
														Subtotal = $593,063

Issue Date FY: 2022 ( Subtotal = $372,303 )
2022	2022	UNIVERSITY OF CALIFORNIA, MERCED	5200 N LAKE RD	MERCED	CA	95344	MERCED	USA	Biomedical Research and Research Training	000	3	5/26/2022	NON-COMPETING CONTINUATION	$372,303
														Subtotal = $372,303

Issue Date FY: 2021 ( Subtotal = $372,641 )
2021	2021	UNIVERSITY OF CALIFORNIA, MERCED	5200 N LAKE RD	MERCED	CA	95344	MERCED	USA	Biomedical Research and Research Training	000	2	5/19/2021	NON-COMPETING CONTINUATION	$372,641
														Subtotal = $372,641

Issue Date FY: 2020 ( Subtotal = $373,120 )
2020	2020	UNIVERSITY OF CALIFORNIA, MERCED	5200 N LAKE RD	MERCED	CA	95344	MERCED	USA	Biomedical Research and Research Training	000	1	7/27/2020	NEW	$373,120
														Subtotal = $373,120

Grand Total All Awards = $2,122,413

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Uncovering the structural underpinnings of function in disordered transcription factor regions

Award Number: R35GM137926

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: 08/01/2020

PERIOD OF PERFORMANCE END DATE: 12/31/2030

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