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The molecular determinants that regulate Cohesin-mediated loop extrusion and stability in vivo

Award Number: R01GM158884
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: 07/10/2026
PERIOD OF PERFORMANCE END DATE: 03/31/2030

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The molecular determinants that regulate Cohesin-mediated loop extrusion and stability in vivo - Project Summary Higher-order organization of chromatin is essential for the regulation of diverse processes in the nucleus, including gene regulation, DNA replication, and DNA repair. At the megabase level, chromosomes are organized into Topologically Associating Domains and chromatin loops through the interplay of the DNA binding protein CTCF and the Cohesin complex. The prevailing model for how CTCF and Cohesin organize chromatin is the loop extrusion model, which posits that Cohesin will bind to chromatin and progressively form a loop over a segment of the genome until stalled by CTCF in an orientation dependent manner. Loop extrusion explains aspects of 3D genome organization observed in genomics experiments and has been observed in vitro using purified proteins. However, loop extrusion has not been directly measured in vivo. This limits our ability to understand what factors regulate the dynamics of chromatin structure in living cells, and how dynamic loop extrusion events contribute to the functional regulation of processes like gene expression and DNA repair. In preliminary data supporting this proposal, the dynamics of loop extrusion were examined in cells that lack the Cohesin subunit NIPBL, which is required for extrusion in vitro. Interestingly, upon rapid degradation of NIPBL, there is heterogeneity in the degree that loops persist on chromatin. This suggests that in vivo, loop extrusion is a regulated process with locus specific effects in the rates of loop extrusion and duration. To better understand the dynamics of chromatin looping, this proposal focuses on the use of novel tools and approaches to understand the dynamics of loop extrusion in vivo. Specific aim 1 will focus on determining factors that contribute to the duration of loops on chromatin in the absence of NIPBL to better understand the molecular factors that regulate loop duration in vivo. Specific aim 2 will employ live cell imaging to examine the dynamics of chromatin loops in the absence of NIPBL to determine whether these are stable, long-lived structural features or are loci capable of NIPBL-independent extrusion. Specific aim 3 focuses on the development of novel strategies to track loop extrusion in vivo using a “molecular recording” strategy based on prior methods for multi-omic analysis of 3D genome organization. Taken together, the experiments outlined in this proposal will greatly increase our understanding of the process of loop extrusion in vivo and the factors that regulate chromatin looping dynamics. In the long term, this will be broadly impactful in shedding light on how dynamic organization of chromatin ultimately impacts processes such as long-range gene regulation, DNA replication, and DNA repair.


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 = $625,589 )
2026	2026	SALK INSTITUTE FOR BIOLOGICAL STUDIES, SAN DIEGO, CALIFORNIA, THE	10010 N TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Biomedical Research and Research Training	000	1	7/7/2026	NEW	$625,589
														Subtotal = $625,589

Grand Total All Awards = $625,589

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The molecular determinants that regulate Cohesin-mediated loop extrusion and stability in vivo

Award Number: R01GM158884

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: 07/10/2026

PERIOD OF PERFORMANCE END DATE: 03/31/2030

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