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Effects of histone ubiquitylation on nucleosome dynamics

Award Number: R01GM130793
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: 08/01/2019
PERIOD OF PERFORMANCE END DATE: 05/31/2024

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Effects of histone ubiquitylation on nucleosome dynamics - Project Summary The long-term goal of this study is to elucidate the molecular mechanisms of how histone ubiquitylation regulates chromatin activity, which remains largely unknown. To understand the fundamental ways in which histone ubiquitylation influences chromatin-mediated biological processes, this project focuses on revealing (1) how histone ubiquitylation affects the structural dynamics of the nucleosome, the fundamental packing unit of chromatin made of ~147 bp DNA, two histone H2A-H2B dimers and one (H3-H4)2 tetramer, and (2) how it regulates the efficiency of hexasome generation by histone chaperone and transcription elongation by RNA polymerase II (Pol II). These studies take advantage of site-specifically ubiquitylated histones and cutting-edge biochemical and single-molecule approaches. An emerging theme in this project is that histone ubiquitylation alters intra-nucleosomal dynamics and thus physically regulates gene accessibility. The preliminary biochemical and single-molecule studies have shown that histone H2BK34 and H2BK120 ubiquitylation accompanies destabilization of the nucleosome structure, inducing labilization of H2A-H2B dimers. In collaboration with a histone acceptor such as histone chaperone Nap1, H2BK34 and H2BK120 ubiquitylation promote dissociation of one of the two H2A-H2B dimers, producing hexasomes that are emerging as critical sub-nucleosomal intermediates in an active chromatin state. The goal of this proposal is to elucidate how histone ubiquitylation alters the nucleosome dynamics and eventually how the changes are implicated in regulating the efficiencies of hexasome generation and transcription elongation. The specific aims are (1) to define the effects of H2BK34/120 ubiquitylation on the structural dynamics of the nucleosome with a recently developed single-molecule structural flexibility test method and (2) to evaluate the effects of H2BK34/ K120ub on (i) the kinetics of hexasome generation by histone chaperone Nap1 and FACT and (ii) the kinetics of transcription elongation in the context of Nap1- and FACT-mediated nucleosome disassembly and reassembly, both at a single-molecule level based on a recently developed transcription elongation monitoring system. This project will result in fundamental understanding on the direct physical roles of histone ubiquitylation in regulating chromatin dynamics.


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: 2025 ( Subtotal = -$18 )
2025	2022	THE PENNSYLVANIA STATE UNIVERSITY	201 OLD MAIN	UNIVERSITY PARK	PA	16802	CENTRE	USA	Biomedical Research and Research Training	000	4	11/26/2024	NON-COMPETING CONTINUATION	-$18
														Subtotal = -$18

Issue Date FY: 2022 ( Subtotal = $299,170 )
2022	2022	PENNSYLVANIA STATE UNIVERSITY, THE	201 OLD MAIN	UNIVERSITY PARK	PA	16802	CENTRE	USA	Biomedical Research and Research Training	000	4	6/1/2022	NON-COMPETING CONTINUATION	$299,170
														Subtotal = $299,170

Issue Date FY: 2021 ( Subtotal = $299,961 )
2021	2021	PENNSYLVANIA STATE UNIVERSITY, THE	201 OLD MAIN	UNIVERSITY PARK	PA	16802	CENTRE	USA	Biomedical Research and Research Training	000	3	5/19/2021	NON-COMPETING CONTINUATION	$299,961
														Subtotal = $299,961

Issue Date FY: 2020 ( Subtotal = $300,722 )
2020	2020	PENNSYLVANIA STATE UNIVERSITY, THE	201 OLD MAIN	UNIVERSITY PARK	PA	16802	CENTRE	USA	Biomedical Research and Research Training	000	2	5/28/2020	NON-COMPETING CONTINUATION	$300,722
														Subtotal = $300,722

Issue Date FY: 2019 ( Subtotal = $301,452 )
2019	2019	PENNSYLVANIA STATE UNIVERSITY, THE	201 OLD MAIN	UNIVERSITY PARK	PA	16802	CENTRE	USA	Biomedical Research and Research Training	000	1	7/26/2019	NEW	$301,452
														Subtotal = $301,452

Grand Total All Awards = $1,201,287

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Effects of histone ubiquitylation on nucleosome dynamics

Award Number: R01GM130793

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: 08/01/2019

PERIOD OF PERFORMANCE END DATE: 05/31/2024

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