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Defining the role of H4ac in mammalian embryogenesis and maternal aging

Award Number: K99HD120619
ORGANIZATION: NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 07/01/2026
PERIOD OF PERFORMANCE END DATE: 06/30/2028

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Defining the role of H4ac in mammalian embryogenesis and maternal aging - SUMMARY Gametes are terminally differentiated cells that carry the information required to establish a totipotent embryo. Epigenetic modifications are integral to maintaining this developmental plasticity, and drastic epigenetic reprogramming occurs soon after fertilization, enabling major transitions in potency. Furthermore, epigenetic dysregulation is a hallmark of aging; accumulation of faulty epigenetic marks contributes to lower oocyte quality and lower numbers of blastocysts formed from aged oocytes. However, the mechanisms by which epigenetic modifications guide reprogramming at fertilization and key transitions in early embryogenesis, and how these mechanisms decay with age, remain poorly understood, in part because of the difficulty in obtaining experimental material at these early stages. Using an ultra-low-scale CUT&Tag method that I developed, my preliminary studies showed that a specific acetylation state of histone H4, H4K12ac, is specifically recruited to SINE-containing active regulatory elements during ZGA and that loss of H4K12ac leads to embryonic arrest and failure to form blastocysts. Notably, H4K12ac is commonly overexpressed in aged oocytes. Activation- associated histone modifications, including several acetylation states of histone H4 (H4ac), are abundant in the zygote, where they are thought to be critical for decondensation of sperm DNA and zygotic genome activation (ZGA). Age-dependent changes in these epigenetic marks are linked to reduced fertility, and global levels of H4ac change with age. However, how H4ac directs distinct cellular transitions during embryogenesis and how defective H4ac regulation in aging could reduce gamete and embryo competence is not fully understood. I hypothesize that H4K12ac-mediated activation of SINEs is important for mammalian embryogenesis and dysregulation of H4K12ac contributes to reduced fertility with maternal aging. The goal of my project is to dissect the mechanism by which H4K12ac and other H4ac states direct embryogenesis and to understand how age-associated defects contribute to reduction of fertility. This investigation will provide crucial insights into early development and ways to extend the female fertility span.


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 = $132,022 )
2026	2026	YALE UNIV	150 MUNSON ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Child Health and Human Development Extramural Research	000	1	6/23/2026	NEW	$132,022
														Subtotal = $132,022

Grand Total All Awards = $132,022

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Defining the role of H4ac in mammalian embryogenesis and maternal aging

Award Number: K99HD120619

ORGANIZATION: NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 07/01/2026

PERIOD OF PERFORMANCE END DATE: 06/30/2028

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