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Function of Kdm4dl-mediated heterochromatin removal in the preimplantation mouse embryo

Award Number: F32HD104442
ORGANIZATION: NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 01/01/2021
PERIOD OF PERFORMANCE END DATE: 12/31/2023

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Function of Kdm4dl-mediated heterochromatin removal in the preimplantation mouse embryo - PROJECT ABSTRACT This project will investigate the function of a currently unstudied histone demethylase, Kdm4dl, in the mouse preimplantation embryo. Many others have shown the developmental importance of activating genes and repeat sequences during a process known as Embryonic Genome Activation (EGA), the moment when the embryo switches on transcription for the first time. EGA involves activation of both protein coding genes as well as repeat sequences that are critical for remodeling the chromatin environment of the early embryo. Yet, even with its known developmental importance, the factors which facilitate EGA are still largely unknown. Here, for the first time, I will investigate the importance of Kdm4dl, which catalytically removes the repressive histone modification H3 Lysine 9 tri-methylation (H3K9me3), in early mouse embryogenesis. I hypothesize that Kdm4dl is required for reprogramming the nuclei of the preimplantation embryo by removing repressive H3K9me3, which facilitates strong activation of EGA-associated transcripts. In line with this hypothesis, my preliminary data demonstrate temporally coordinated Kdm4dl protein expression during the 2-cell stage, when EGA occurs. Moreover, Kdm4dl over-expression is sufficient to demethylate H3K9me3 in embryonic stem cells leading to strong activation of EGA-associate transcripts and repeats. Combined, these preliminary data provide further support for pursuing the project’s hypothesis further. The two outstanding questions I aim to address are: 1. Is Kdm4dl expression sufficient to reprogram cells to a state of expanded potential, consistent with a 2-cell-like totipotent state? and 2. Is Kdm4dl expression necessary for H3K9 demethylation and activation of EGA-associated genes and repeats in vivo? To aid in addressing these questions, I have developed both an innovative embryonic stem cell system which recapitulates the temporal dynamics of Kdm4dl expression in the preimplantation embryo, and I have also established a Kdm4dl knockout mouse model. This research project, combined with my detailed training plan, is consistent with my technical and professional goals of becoming an independent academic investigator studying chromatin dynamics in the early mammalian embryo, with relevance to human fertility.


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 = -$1 )
2025	2023	UNIVERSITY OF UTAH	201 PRESIDENTS CIR	SALT LAKE CITY	UT	84112	SALT LAKE	USA	Child Health and Human Development Extramural Research	000	3	10/23/2024	NON-COMPETING CONTINUATION	-$1
														Subtotal = -$1

Issue Date FY: 2023 ( Subtotal = $71,792 )
2023	2023	UNIVERSITY OF UTAH, THE	201 PRESIDENTS CIR	SALT LAKE CITY	UT	84112	SALT LAKE	USA	Child Health and Human Development Extramural Research	001	3	2/7/2023	NON-COMPETING CONTINUATION	$1,990
2023	2023	UNIVERSITY OF UTAH, THE	201 PRESIDENTS CIR	SALT LAKE CITY	UT	84112	SALT LAKE	USA	Child Health and Human Development Extramural Research	000	3	12/8/2022	NON-COMPETING CONTINUATION	$69,802
														Subtotal = $71,792

Issue Date FY: 2022 ( Subtotal = $67,582 )
2022	2022	UNIVERSITY OF UTAH, THE	201 PRESIDENTS CIR	SALT LAKE CITY	UT	84112	SALT LAKE	USA	Child Health and Human Development Extramural Research	001	2	4/22/2022	NON-COMPETING CONTINUATION	$1,191
2022	2022	UNIVERSITY OF UTAH, THE	201 PRESIDENTS CIR	SALT LAKE CITY	UT	84112	SALT LAKE	USA	Child Health and Human Development Extramural Research	000	2	12/14/2021	NON-COMPETING CONTINUATION	$66,390
2022	2022	UNIVERSITY OF UTAH, THE	201 PRESIDENTS CIR	SALT LAKE CITY	UT	84112	SALT LAKE	USA	Child Health and Human Development Extramural Research	002	2	6/23/2022	NON-COMPETING CONTINUATION	$1
														Subtotal = $67,582

Issue Date FY: 2021 ( Subtotal = $65,994 )
2021	2021	UNIVERSITY OF UTAH, THE	201 PRESIDENTS CIR	SALT LAKE CITY	UT	84112	SALT LAKE	USA	Child Health and Human Development Extramural Research	002	1	2/12/2021	NEW	$1,068
2021	2021	UNIVERSITY OF UTAH, THE	201 PRESIDENTS CIR	SALT LAKE CITY	UT	84112	SALT LAKE	USA	Child Health and Human Development Extramural Research	000	1	11/10/2020	NEW	$64,926
2021	2021	UNIVERSITY OF UTAH, THE	201 PRESIDENTS CIR	SALT LAKE CITY	UT	84112	SALT LAKE	USA	Child Health and Human Development Extramural Research	001	1	11/10/2020	NEW	$0
														Subtotal = $65,994

Grand Total All Awards = $205,367

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Function of Kdm4dl-mediated heterochromatin removal in the preimplantation mouse embryo

Award Number: F32HD104442

ORGANIZATION: NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 01/01/2021

PERIOD OF PERFORMANCE END DATE: 12/31/2023

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