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Hormonal Regulation of Mammalian Gene Expression

Award Number: R01DK057978
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 04/01/1979
PERIOD OF PERFORMANCE END DATE: 03/31/2025

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Hormonal Regulation of Mammalian Gene Expression - Nuclear receptors (NRs) influence development and physiology by controlling patterns of gene expression via ligand-directed chromatin modifications. The resultant induced epigenomic state mobilizes networks of genes to engender unique cell functions and physiology. This proposal extends on previous studies that elucidated the roles of the NRs PPARd and ERRa/g in context-specific transcriptional activities that reprogram skeletal muscle metabolism and physiology to increase endurance performance. A central focus of exercise physiology has been the functional association of induced transcriptional programs with changes in histone acetylation, including understanding how the activation of PPARd and ERRa/g and their coactivator PGC1a drive oxidative metabolic programs that lead to increased endurance performance. In contrast, little is known about the potential contributions of repressive programs and the expected histone deacetylation. BCL6 was identified as a novel, exercise-responsive transcriptional repressor in both humans and mice, however its importance in muscle physiology has not been explored. Interestingly, an interaction between BCL6 and PPARd, the master regulator of fatty acid substrate utilization, has been shown in other cell types suggesting that BCL6 may have dual roles in skeletal muscle; effecting transcriptional outcomes through its direct chromatin binding as well as indirectly by modulating the PPARd transcriptional program. This proposal utilizes pharmacologic strategies and muscle-specific genetic knockout mouse models in combination with epigenetic and transcriptional mapping techniques to delineate BCL6’s function in exercise physiology. In Aim 1, the BCL6 transcriptional complex will be characterized using state-of-the-art APEX2 proximity labeling techniques in WT and PPARd KO primary skeletal muscle myotubes with and without pharmacologic agents targeting BCL6. Changes in the BCL6 complex in response to ligands will be correlated with altered epigenomic and gene expression states to associate specific complexes with functional outcomes. In Aim 2, the contributions of BCL6 to exercise-induced physiologic and transcriptional changes will be determined using genetic (muscle-specific Bcl6 knockout mice) and pharmacologic (BCL6 inhibitor) loss-of-function mouse models, while related studies in muscle-specific Ppard knockout mice will distinguish the PPARd dependent and independent effects. Lastly, Aim 3 will exploit the advances of the CUT&RUN technology to map the BCL6 chromatin binding sites in sedentary and exercised skeletal muscle. Combined with the changes induced in PPARd and ERRg binding, in addition to alterations in histone regulatory marks, these studies will molecularly dissect the competing repressive and activating transcriptional programs in muscle. Moreover, associating these findings with the transcriptional complexes identified in Aim 1 and the transcriptomics data from Aim 2 will provide a comprehensive view of BCL6-driven transcriptional repression and its contribution to transcriptional regulation of skeletal muscle in both the resting and exercise state.


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 = -$327 )
2025	2024	SALK INSTITUTE FOR BIOLOGICAL STUDIES, SAN DIEGO, CALIFORNIA, THE	10010 N TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	45	5/14/2025	NON-COMPETING CONTINUATION	-$327
														Subtotal = -$327

Issue Date FY: 2024 ( Subtotal = $627,220 )
2024	2024	SALK INSTITUTE FOR BIOLOGICAL STUDIES, SAN DIEGO, CALIFORNIA, THE	10010 N TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	45	5/3/2024	NON-COMPETING CONTINUATION	$39,203
2024	2024	SALK INSTITUTE FOR BIOLOGICAL STUDIES, SAN DIEGO, CALIFORNIA, THE	10010 N TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	45	3/22/2024	NON-COMPETING CONTINUATION	$588,017
														Subtotal = $627,220

Issue Date FY: 2023 ( Subtotal = $661,761 )
2023	2023	SALK INSTITUTE FOR BIOLOGICAL STUDIES, SAN DIEGO, CALIFORNIA, THE	10010 N TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	44	3/17/2023	NON-COMPETING CONTINUATION	$661,761
														Subtotal = $661,761

Issue Date FY: 2022 ( Subtotal = $668,399 )
2022	2022	SALK INSTITUTE FOR BIOLOGICAL STUDIES, SAN DIEGO, CALIFORNIA, THE	10010 N TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	43	3/29/2022	NON-COMPETING CONTINUATION	$668,399
														Subtotal = $668,399

Issue Date FY: 2021 ( Subtotal = $665,000 )
2021	2021	SALK INSTITUTE FOR BIOLOGICAL STUDIES, SAN DIEGO, CALIFORNIA, THE	10010 N TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	42	5/3/2021	COMPETING CONTINUATION	$665,000
														Subtotal = $665,000

Issue Date FY: 2000 ( Subtotal = $592,296 )
2000	2000	SALK INSTITUTE FOR BIOLOGICAL STUDIES	10010 N TORREY PINES ROAD	LA JOLLA	CA	92037	SAN DIEGO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	22	3/27/2000	OTHER REVISION	$592,296
														Subtotal = $592,296

Grand Total All Awards = $3,214,349

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Hormonal Regulation of Mammalian Gene Expression

Award Number: R01DK057978

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 04/01/1979

PERIOD OF PERFORMANCE END DATE: 03/31/2025

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