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Mechanism of chromatin accessibility, 3D chromosome organization, and their functions in gene regulation

Award Number: R35GM139654
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: 11/30/2030

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Mechanism of chromatin accessibility, 3D chromosome organization, and their functions in gene regulation - Project Summary / Abstract The overall theme of my research program is to unravel the mechanisms underlying chromatin structure and understand its role in gene regulation. Our approach tackles this challenge on two interconnected levels: at the chromatin / nucleosome level, we investigate the mechanisms driving nucleosome depletion and chromatin accessibility, while at the higher-order chromosome level, we explore the structure and dynamics of 3D genome organization and its functions in various nuclear processes, particularly transcriptional regulation. Over the past five years, primarily supported by the previous R35, we have made significant progress in both areas, yielding valuable new insights and innovative methodologies. We have also expanded our research from budding yeast to mammalian cells. These advances serve as the foundation for this proposal. Theme1: Pioneer factors (PFs) can invade into nucleosomes and increase chromatin accessibility near their binding sites and often serve as master regulators for gene expression during differentiation. Despite their essential functions, only a handful of PFs have been identified, and the mechanism underlying the pioneer activity remains poorly understood. The long-term goal of this theme is to systematically identify PFs and characterize their pioneer activities in health and disease cells, and to develop a full mechanistic understanding of how they access their nucleosomal binding sites, generate accessible chromatin, and regulate gene expression. Our recent studies have shed light on the mechanisms of PF invasion, their coordination with chromatin remodelers, and their targeting specificity. In the next five years, we plan to 1) Identify PFs responsible for generating constitutive open regions in human cells using integrated synthetic oligo (ISO) technology, 2) investigate the mechanism of PF binding cooperativity, 3) further our understanding of PF/TF specificity towards chromatin remodelers, and 4) explore intriguing connections between cohesin and PF/TF nucleosome invasion. Theme2: Imaging and 3C-based methods have revealed intricate chromosome folding patterns with extensive long-range intra- and inter-chromosomal interactions, yet the functional significance of these 3D chromosomal contacts remains elusive. The long-term goal of this theme is to understand the formation mechanism of high- order chromosome structures and dissect their functions in gene regulation and other nuclei processes. Recently, we developed innovative methods for detecting and manipulating chromosomal interactions in yeast, and uncovered connections between TF condensates, 3D genome organization, and gene regulation. Building on these advancements, we plan to extend one of our methods, chemically induced chromosomal interactions (CICI), from budding yeast to mammalian cells. This approach will allow us to study chromosome dynamics across various 3D structures, and explore the relationship between heterochromatin condensates, genome organization, and gene repression.


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 = $583,193 )
2026	2026	THE PENNSYLVANIA STATE UNIVERSITY	201 OLD MAIN	UNIVERSITY PARK	PA	16802	CENTRE	USA	Biomedical Research and Research Training	002	6	2/12/2026	COMPETING CONTINUATION	$583,193
2026	2025	THE PENNSYLVANIA STATE UNIVERSITY	201 OLD MAIN	UNIVERSITY PARK	PA	16802	CENTRE	USA	Biomedical Research and Research Training	000	5	10/10/2025	NON-COMPETING CONTINUATION	$0
2026	2025	THE PENNSYLVANIA STATE UNIVERSITY	201 OLD MAIN	UNIVERSITY PARK	PA	16802	CENTRE	USA	Biomedical Research and Research Training	001	5	2/11/2026	NON-COMPETING CONTINUATION	$0
														Subtotal = $583,193

Issue Date FY: 2025 ( Subtotal = $658,233 )
2025	2025	THE PENNSYLVANIA STATE UNIVERSITY	201 OLD MAIN	UNIVERSITY PARK	PA	16802	CENTRE	USA	Biomedical Research and Research Training	002	5	5/28/2025	SUPPLEMENT FOR EXPANSION	$57,794
2025	2025	THE PENNSYLVANIA STATE UNIVERSITY	201 OLD MAIN	UNIVERSITY PARK	PA	16802	CENTRE	USA	Biomedical Research and Research Training	003	5	8/14/2025	NON-COMPETING CONTINUATION	$60,044
2025	2025	THE PENNSYLVANIA STATE UNIVERSITY	201 OLD MAIN	UNIVERSITY PARK	PA	16802	CENTRE	USA	Biomedical Research and Research Training	001	5	12/6/2024	NON-COMPETING CONTINUATION	$540,395
2025	2024	THE PENNSYLVANIA STATE UNIVERSITY	201 OLD MAIN	UNIVERSITY PARK	PA	16802	CENTRE	USA	Biomedical Research and Research Training	000	4	11/4/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $658,233

Issue Date FY: 2024 ( Subtotal = $600,439 )
2024	2024	THE PENNSYLVANIA STATE UNIVERSITY	201 OLD MAIN	UNIVERSITY PARK	PA	16802	CENTRE	USA	Biomedical Research and Research Training	001	4	6/27/2024	NON-COMPETING CONTINUATION	$60,044
2024	2024	THE PENNSYLVANIA STATE UNIVERSITY	201 OLD MAIN	UNIVERSITY PARK	PA	16802	CENTRE	USA	Biomedical Research and Research Training	000	4	12/29/2023	NON-COMPETING CONTINUATION	$540,395
														Subtotal = $600,439

Issue Date FY: 2023 ( Subtotal = $618,104 )
2023	2023	THE PENNSYLVANIA STATE UNIVERSITY	201 OLD MAIN	UNIVERSITY PARK	PA	16802	CENTRE	USA	Biomedical Research and Research Training	002	3	9/12/2023	SUPPLEMENT FOR EXPANSION	$17,665
2023	2023	PENNSYLVANIA STATE UNIVERSITY, THE	201 OLD MAIN	UNIVERSITY PARK	PA	16802	CENTRE	USA	Biomedical Research and Research Training	001	3	3/21/2023	NON-COMPETING CONTINUATION	$60,044
2023	2023	PENNSYLVANIA STATE UNIVERSITY, THE	201 OLD MAIN	UNIVERSITY PARK	PA	16802	CENTRE	USA	Biomedical Research and Research Training	000	3	12/14/2022	NON-COMPETING CONTINUATION	$540,395
														Subtotal = $618,104

Issue Date FY: 2022 ( Subtotal = $820,105 )
2022	2022	PENNSYLVANIA STATE UNIVERSITY, THE	201 OLD MAIN	UNIVERSITY PARK	PA	16802	CENTRE	USA	Biomedical Research and Research Training	002	2	7/25/2022	SUPPLEMENT FOR EXPANSION	$219,666
2022	2022	PENNSYLVANIA STATE UNIVERSITY, THE	201 OLD MAIN	UNIVERSITY PARK	PA	16802	CENTRE	USA	Biomedical Research and Research Training	001	2	7/21/2022	NON-COMPETING CONTINUATION	$60,044
2022	2022	PENNSYLVANIA STATE UNIVERSITY, THE	201 OLD MAIN	UNIVERSITY PARK	PA	16802	CENTRE	USA	Biomedical Research and Research Training	000	2	12/8/2021	NON-COMPETING CONTINUATION	$540,395
														Subtotal = $820,105

Issue Date FY: 2021 ( Subtotal = $493,438 )
2021	2021	PENNSYLVANIA STATE UNIVERSITY, THE	201 OLD MAIN	UNIVERSITY PARK	PA	16802	CENTRE	USA	Biomedical Research and Research Training	000	1	12/30/2020	NEW	$493,438
														Subtotal = $493,438

Grand Total All Awards = $3,773,512

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Mechanism of chromatin accessibility, 3D chromosome organization, and their functions in gene regulation

Award Number: R35GM139654

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: 11/30/2030

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