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Phase Separation: A New Phase in Decoding Enhancer-dependent Critical Transcriptional Programs by Nuclear Receptors

Award Number: R01DK039949
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

Group Awards By Issue Date FY or Funding FY:

View Award Abstract

Mammalian cells exhibit a precise gene regulation process, during which enhancers play critical roles in mediating rapid gene activation in response to different signals. Indeed, much of our knowledge about gene transcriptional control comes from the long-standing investigation of the actions of nuclear receptors, well exemplified by estrogen 17ß-estradiol (E2)-dependent activation of transcriptional programs. This program is controlled virtually entirely by activation of a cohort of ~1000 robustly activated ERa-bound enhancers. Under physiological conditions, many signals are pulsatile, including ligands for nuclear receptors such as ERa, representing a continuum from transient, acute stimulation to chronic stimulation. We have found that the acute 17ß-estradiol (E2)-dependent activation of functional enhancers requires assembly of an eRNA-dependent ribonucleoprotein (eRNP) complex, referred to as the MegaTrans complex. A transformative, newly emerging concept, to which we are pleased to have contributed, is that acute signal of ligand-dependent activation of target enhancers causes them to form an RNA-protein condensate, with features of phase separation, that results in cooperative activation of other homotypic enhancers separated by multiple TADs and, even in other chromosomes. In contrast, chronic signal/ligand activation results in loss of the dynamic RNP condensate at the enhancers, loss of induced proximity of homotypic enhancers observed with acute activation, with enhancer activation function now confined to the nearby cognate target gene promoters. We will use global genomic, proteomic, and real time, single nucleus approaches, with appropriate informatics, to examine the patterns of enhancer activation, potential interactions in acute vs chronic ligand-dependent activation, relationship to localization in phase-separated subnuclear architectural structures and patterns of movement by single molecule imaging. Our goal is to provide a paradigm-shifting insight into ligand/hormone-regulated transcriptional programs, based on this multidisciplinary approach.


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: 2024 ( Subtotal = $457,359 )
2024	2024	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	42	3/4/2024	NON-COMPETING CONTINUATION	$457,359
														Subtotal = $457,359

Issue Date FY: 2023 ( Subtotal = $520,642 )
2023	2023	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DRIVE	LA JOLLA	CA	92093	SAN DIEGO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	41	3/8/2023	NON-COMPETING CONTINUATION	$520,642
														Subtotal = $520,642

Issue Date FY: 2022 ( Subtotal = $532,097 )
2022	2022	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	40	2/21/2022	NON-COMPETING CONTINUATION	$478,885
2022	2022	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	40	3/24/2022	NON-COMPETING CONTINUATION	$53,212
														Subtotal = $532,097

Issue Date FY: 2021 ( Subtotal = $542,947 )
2021	2021	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	39	3/15/2021	COMPETING CONTINUATION	$542,947
														Subtotal = $542,947

Issue Date FY: 2000 ( Subtotal = $350,216 )
2000	2000	UNIVERSITY OF CALIFORNIA-SAN DIEGO	9500 GILMAN DRIVE	LA JOLLA	CA	92093	SAN DIEGO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	18	3/27/2000	NON-COMPETING CONTINUATION	$350,216
														Subtotal = $350,216

Issue Date FY: 1999 ( Subtotal = $459,049 )
1999	1999	UNIVERSITY OF CALIFORNIA-SAN DIEGO	9500 GILMAN DRIVE	LA JOLLA	CA	92093	SAN DIEGO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	17	12/31/1998	NON-COMPETING CONTINUATION	$396,699
1999	1999	UNIVERSITY OF CALIFORNIA-SAN DIEGO	9500 GILMAN DRIVE	LA JOLLA	CA	92093	SAN DIEGO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	17	2/3/1999	SUPPLEMENT FOR EXPANSION	$62,350
														Subtotal = $459,049

Issue Date FY: 1998 ( Subtotal = $447,791 )
1998	1998	UNIVERSITY OF CALIFORNIA-SAN DIEGO	9500 GILMAN DRIVE	LA JOLLA	CA	92093	SAN DIEGO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	16	12/15/1997	SUPPLEMENT FOR EXPANSION	$62,350
1998	1998	UNIVERSITY OF CALIFORNIA-SAN DIEGO	9500 GILMAN DRIVE	LA JOLLA	CA	92093	SAN DIEGO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	16	12/8/1997	NON-COMPETING CONTINUATION	$385,441
														Subtotal = $447,791

Grand Total All Awards = $3,310,101

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Phase Separation: A New Phase in Decoding Enhancer-dependent Critical Transcriptional Programs by Nuclear Receptors

Award Number: R01DK039949

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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