NIH grant: An enhancer-driven epigenetic memory promotes metabolic resilience (1R01AG097608-01)

retained text

NIH grant 1R01AG097608-01: An enhancer-driven epigenetic memory promotes metabolic resilience
Institute: {'code': 'AG', 'abbreviation': 'NIA', 'name': 'National Institute on Aging', 'admin_org_id': '12500002', 'admin_funding_url': ''}. PI: Wenbo  Li. Award: $689188.
Start: 2026-08-15T00:00:00.
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.

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