Sunday, July 6, 2025 7/6/2025

Dissecting genetic determinants of epigenetic instability in pluripotent stem cells

Award Number: R01GM145864
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 04/15/2022
PERIOD OF PERFORMANCE END DATE: 02/28/2026

Group Awards By:

View Award Description

Dissecting genetic determinants of epigenetic instability in pluripotent stem cells - Project Summary The remarkable ability of pluripotent stem cells (PSCs) to give rise to a plethora of fully functional somatic cell types becomes progressively impaired upon ex vivo culture by aberrant gain or loss of DNA methylation marks at essential developmental gene loci. This pervasive epigenetic instability represents a significant hurdle for biomedical applications using PSCs, but the underlying molecular reasons remain almost entirely unknown. An important example for epigenetic instability in PSCs is loss of genomic imprinting, an essential gene regulatory mechanism in mammals. By combining transgenic reporter alleles for imprint stability with mouse genetics, we found that imprint dysregulation in PSCs is caused by identifiable genetic variants that affect trans acting chromatin regulators. The goal of this proposal is to develop a comprehensive molecular understanding on how specific genetic variants affect the stability of vital epigenetic marks in PSCs. To work towards this goal, we will first functionally dissect the causal variants within a genomic susceptibility region that we discovered and which drives locus-specific DNA hypermethylation and loss of developmental potential. This will allow us to pinpoint gene regulatory features that predispose imprinted and other genes to aberrant gain of DNA methylation (Aim 1). We will then use genetic mapping in hybrid PSCs to discover quantitative trait loci that can protect against detrimental DNA hypomethylation and validate the function of associated gene products in both mouse and human pluripotent cells (Aim 2). Finally, we will model the genetics of imprint stability in a panel of PSCs with highly diverse yet well-characterized genomes. This will enable us to dissect the molecular regulation of epigenetic stability in complex genetic backgrounds resembling the human population and help us to establish new biomarkers for the identification of culture conditions that preserve developmental potential in PSCs of unknown genetic background (Aim 3). Our work will establish novel conceptual and mechanistic frameworks for the detrimental epigenetic vulnerability of pluripotent cells, which will aid the safe and reliable use of these cells to study developmental and disease processes. In addition, our findings will have relevance for a wide range of human diseases and developmental syndromes characterized by epigenetic instability.


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 = $380,602 )
2025	2025	WEILL MEDICAL COLLEGE OF CORNELL UNIVERSITY	575 LEXINGTON AVE FL 9	NEW YORK	NY	10022	NEW YORK	USA	Biomedical Research and Research Training	000	4	2/26/2025	NON-COMPETING CONTINUATION	$380,602
														Subtotal = $380,602

Issue Date FY: 2024 ( Subtotal = $423,731 )
2024	2024	WEILL MEDICAL COLLEGE OF CORNELL UNIVERSITY	575 LEXINGTON AVE FL 9	NEW YORK	NY	10022	NEW YORK	USA	Biomedical Research and Research Training	000	3	2/23/2024	NON-COMPETING CONTINUATION	$381,358
2024	2024	WEILL MEDICAL COLLEGE OF CORNELL UNIVERSITY	575 LEXINGTON AVE FL 9	NEW YORK	NY	10022	NEW YORK	USA	Biomedical Research and Research Training	001	3	7/11/2024	NON-COMPETING CONTINUATION	$42,373
														Subtotal = $423,731

Issue Date FY: 2023 ( Subtotal = $399,050 )
2023	2023	WEILL MEDICAL COLLEGE OF CORNELL UNIVERSITY	1300 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Biomedical Research and Research Training	000	2	2/7/2023	NON-COMPETING CONTINUATION	$399,050
														Subtotal = $399,050

Issue Date FY: 2022 ( Subtotal = $421,830 )
2022	2022	WEILL MEDICAL COLLEGE OF CORNELL UNIVERSITY	1300 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Biomedical Research and Research Training	000	1	4/14/2022	NEW	$408,287
2022	2022	WEILL MEDICAL COLLEGE OF CORNELL UNIVERSITY	1300 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Biomedical Research and Research Training	001	1	7/29/2022	NEW	$13,543
														Subtotal = $421,830

Grand Total All Awards = $1,625,213

Top

All Categories

About

Search

Reports

Data Submission

Award Information

Dissecting genetic determinants of epigenetic instability in pluripotent stem cells

Award Number: R01GM145864

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 04/15/2022

PERIOD OF PERFORMANCE END DATE: 02/28/2026

Federal Websites

Department of Health & Human Services

HHS Operating Divisions

HHS Staff Divisions

Download A Document Viewer