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Germline Utx mutation as a model for transgenerational epigenetic inheritance

Award Number: R01HD098128
ORGANIZATION: NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 05/01/2020
PERIOD OF PERFORMANCE END DATE: 01/31/2025

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Germline Utx mutation as a model for transgenerational epigenetic inheritance - PROJECT SUMMARY Male gametes transmit the paternal genome to the next generation. At the same time, they also carry epigenetic information that is passed to the zygote at fertilization. A major unanswered question is whether this inherited epigenetic information influences gene expression, phenotype, and disease susceptibility in offspring. We have found that knocking out the chromatin regulator gene Utx in the mouse male germ line leads to reduced survival and increased rates of tumor formation in offspring, even when offspring do not themselves carry a Utx mutation. This proposal will test the hypothesis that loss of Utx in male germ cells induces epigenetic changes in the gametes that alter gene expression after fertilization and ultimately result in the increased tumor susceptibility observed in offspring. Specifically, the experiments proposed here will examine genome-wide changes in histone modification, DNA methylation, and gene expression in developing and mature male gametes of Utx conditional knockouts (Aim 1); evaluate gene expression and phenotypic effects in embryos of the next generation at the preimplantation and perinatal stages (Aim 2); and define changes in histone modification, DNA methylation, and gene expression in developing and mature germ cells of offspring in order to determine if these changes can persist across multiple generations (Aim 3). The ultimate goal of this study is to understand how changes in the development and gene regulatory state of mammalian male germ cells can impact phenotype and disease in progeny. In the past, this question has been addressed primarily by manipulating the paternal environment using chemical or nutritional exposures, which are difficult to control precisely. In contrast, this study will employ a simple, well-defined and highly reproducible genetic manipulation that can be used to generate germline epigenetic changes. The proposed experiments will elucidate a new mechanism by which epigenetic misregulation in male gametes can contribute to male infertility, a priority area for NICHD. The results will also frame a new mechanism for non-genetic inheritance of disease susceptibility, with broad implications for the etiology and epidemiology of common diseases such as cancer and diabetes.


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 = -$588 )
2025	2024	YALE UNIV	150 MUNSON ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Child Health and Human Development Extramural Research	000	5	5/1/2025	NON-COMPETING CONTINUATION	-$588
														Subtotal = -$588

Issue Date FY: 2024 ( Subtotal = $390,936 )
2024	2024	YALE UNIV	150 MUNSON ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Child Health and Human Development Extramural Research	001	5	5/2/2024	NON-COMPETING CONTINUATION	$35,537
2024	2024	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Child Health and Human Development Extramural Research	000	5	1/30/2024	NON-COMPETING CONTINUATION	$355,399
														Subtotal = $390,936

Issue Date FY: 2023 ( Subtotal = $394,886 )
2023	2023	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Child Health and Human Development Extramural Research	000	4	2/3/2023	NON-COMPETING CONTINUATION	$394,886
														Subtotal = $394,886

Issue Date FY: 2022 ( Subtotal = $394,886 )
2022	2022	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Child Health and Human Development Extramural Research	001	3	4/22/2022	NON-COMPETING CONTINUATION	$39,491
2022	2022	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Child Health and Human Development Extramural Research	000	3	1/31/2022	NON-COMPETING CONTINUATION	$355,395
														Subtotal = $394,886

Issue Date FY: 2021 ( Subtotal = $390,652 )
2021	2021	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Child Health and Human Development Extramural Research	001	2	2/10/2021	NON-COMPETING CONTINUATION	$31,890
2021	2021	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Child Health and Human Development Extramural Research	000	2	1/27/2021	NON-COMPETING CONTINUATION	$358,762
														Subtotal = $390,652

Issue Date FY: 2020 ( Subtotal = $398,625 )
2020	2020	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Child Health and Human Development Extramural Research	000	1	4/23/2020	NEW	$398,625
														Subtotal = $398,625

Grand Total All Awards = $1,969,397

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Germline Utx mutation as a model for transgenerational epigenetic inheritance

Award Number: R01HD098128

ORGANIZATION: NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 05/01/2020

PERIOD OF PERFORMANCE END DATE: 01/31/2025

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