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An enhancer-driven epigenetic memory promotes metabolic resilience

Award Number: R01AG097608
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/15/2026
PERIOD OF PERFORMANCE END DATE: 07/31/2031

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An enhancer-driven epigenetic memory promotes metabolic resilience - ABSTRACT/SUMMARY Parity, gravidity, and oral contraceptive usage history can impact women's later-life susceptibility to metabolic diseases such as diabetes, fatty liver, and dyslipidemia. However, the direction and extent of these impacts remain incompletely characterized. Understanding mechanisms underlying such persistent gene-environment interactions is important for later-life disease prevention. We find that high-level estrogen exposure to mice, mimicking pregnancy, initiated a hepatic epigenetic memory, defined by persistent chromatin accessibility and histone hyperacetylation at an intragenic enhancer of a transcription factor (TF) BNC2, allowing sustained BNC2 upregulation months after cessation of estrogen exposure (washout). This epigenetic memory remained latent after washout as it caused little transcriptomic differences, but can be retrieved after a second hit with a high- fat diet (HFD), leading to transcriptomic changes and metabolic resilience, including improved glucose tolerance, reduced liver triglycerides, and lower blood cholesterol levels. Hepatocyte-specific depletion of estrogen receptors (ERα/β) or epigenetic suppression of the BNC2 enhancer with CRISPRi nullified the metabolic resilience, while targeted elevation of histone acetylation at the BNC2 enhancer recapitulated the metabolic resilience. The enhancer is evolutionarily conserved, contains binding sites for ERα and BNC2, and can be activated by BNC2 overexpression. We hypothesize that pregnancy-associated high estrogen initiates an epigenetic memory in the liver at the BNC2 enhancer through ER, which is maintained by BNC2 positive self- feedback and retrieved by overnutrition, leading to transcriptomic changes and enhanced metabolic resilience. We will determine how the hepatic epigenetic memory is initiated by high-level estrogen or pregnancy, how it is maintained post-cessation of high estrogen or pregnancy, and how it is retrieved and affects metabolism. Compared to extensive studies on the immediate effects of low estrogen exposure in the context of menopause, the enduring effects of pregnancy-associated high estrogen exposure on women's later-life disease susceptibility are underexplored. We aim to fill the knowledge gap by elucidating the initiation, maintenance, and retrieval of an unexpected epigenetic memory following prior high-level estrogen exposure or pregnancy experience. The success of this work will delineate how transient signaling events in adulthood can exert prolonged influence on later-life physiology, with significant implications for women's metabolic health.


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 = $689,188 )
2026	2026	BAYLOR COLLEGE OF MEDICINE	1 BAYLOR PLZ	HOUSTON	TX	77030	HARRIS	USA	Aging Research	000	1	8/12/2026	NEW	$689,188
														Subtotal = $689,188

Grand Total All Awards = $689,188

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An enhancer-driven epigenetic memory promotes metabolic resilience

Award Number: R01AG097608

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 08/15/2026

PERIOD OF PERFORMANCE END DATE: 07/31/2031

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