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X-chromosome Inactivation Catalyzed by Genes that Escape X-inactivation

Award Number: R01GM124571
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: 09/08/2017
PERIOD OF PERFORMANCE END DATE: 11/30/2027

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X-chromosome Inactivation Catalyzed by Genes that Escape X-inactivation - Project Summary/Abstract The Y chromosome is widely believed to be the sole source of sex differences in mammals. Emerging work, including from our group, however, also implicates X-linked genes in inducing sexually dimorphic gene expression. Although most X-linked genes are expressed equally between females and males through the transcriptional inactivation of one of the two X chromosomes in females, some escape X-inactivation and are subject to higher expression in females. Differences in the levels of expression of X-linked genes between the sexes may thus contribute to sex differences. The long-term goal of this proposal is to elucidate mechanisms of sex-biased transcriptional regulation. In the prior round of funding, we found that the higher expression in females of the X-inactivation escapee Kdm5c induces X-inactivation selectively in females and not males in an evolutionarily conserved. We have also accumulated preliminary data suggesting that whereas at a higher expression dose KDM5C induces X-inactivation, at a lower dose it paradoxically first prevents inactivation of the active X chromosome in males as well as in females. We further found that KDM5C also regulates autosomal genes in a sex-biased manner. The overall objective of this proposal, which constitute the next steps toward attaining our long-term goal, is to determine mechanistically how KDM5C functions in a sex- biased manner. Our central hypothesis is that KDM5C regulates gene expression in a sex-biased manner on the X chromosomes as well as autosomes through dose-dependent and locus-specific H3K4me2/3 demethylation. The rationale for this proposal is that the mechanistic dissection of KDM5C function will inform the hormone-independent regulation of sexually dimorphic gene expression. The proposal's central hypothesis will be tested by the following two specific aims: 1) Determine how KDM5C orchestrates the selection of the active and the inactive X chromosome in mouse embryos and stem cells; and, 2) Mechanistically dissect the functions of KDM5C in hormone-independent regulation of sex-biased gene expression in mouse embryos and differentiating embryonic stem cells. The Aims will be tested by ablating or tuning the expression of KDM5C protein and connecting changes in histone H3K4me1/2/3 modifications and their downstream effectors to changes in the expression of the KDM5C target loci genome-wide. The proposed research is innovative because it promises a novel mechanism underlying mammalian sex differences, including in the divergent transcriptional fates of the X chromosomes, using cutting-edge chromatin and single-cell transcriptional profiling technologies. The significance of the proposal is that it will identify novel dose-dependent genetic and epigenetic mechanisms that contribute to sex differences independently of hormones.


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 = $385,515 )
2026	2026	REGENTS OF THE UNIVERSITY OF MICHIGAN	1109 GEDDES AVE STE 3300	ANN ARBOR	MI	48109	WASHTENAW	USA	Biomedical Research and Research Training	000	7	12/11/2025	NON-COMPETING CONTINUATION	$385,515
														Subtotal = $385,515

Issue Date FY: 2025 ( Subtotal = $471,182 )
2025	2025	REGENTS OF THE UNIVERSITY OF MICHIGAN	1109 GEDDES AVE, SUITE 3300	ANN ARBOR	MI	48109	WASHTENAW	USA	Biomedical Research and Research Training	000	6	11/22/2024	NON-COMPETING CONTINUATION	$385,516
2025	2025	REGENTS OF THE UNIVERSITY OF MICHIGAN	1109 GEDDES AVE STE 3300	ANN ARBOR	MI	48109	WASHTENAW	USA	Biomedical Research and Research Training	002	6	8/12/2025	NON-COMPETING CONTINUATION	$42,833
2025	2025	REGENTS OF THE UNIVERSITY OF MICHIGAN	1109 GEDDES AVE STE 3300	ANN ARBOR	MI	48109	WASHTENAW	USA	Biomedical Research and Research Training	001	6	8/12/2025	NON-COMPETING CONTINUATION	$42,833
														Subtotal = $471,182

Issue Date FY: 2024 ( Subtotal = $478,241 )
2024	2024	REGENTS OF THE UNIVERSITY OF MICHIGAN	1109 GEDDES AVE, SUITE 3300	ANN ARBOR	MI	48109	WASHTENAW	USA	Biomedical Research and Research Training	000	5	12/14/2023	COMPETING CONTINUATION	$428,349
2024	2024	REGENTS OF THE UNIVERSITY OF MICHIGAN	1109 GEDDES AVE, SUITE 3300	ANN ARBOR	MI	48109	WASHTENAW	USA	Biomedical Research and Research Training	001	5	5/14/2024	SUPPLEMENT FOR EXPANSION	$49,892
														Subtotal = $478,241

Issue Date FY: 2023 ( Subtotal = -$916 )
2023	2020	REGENTS OF THE UNIVERSITY OF MICHIGAN	1109 GEDDES AVE, SUITE 3300	ANN ARBOR	MI	48109	WASHTENAW	USA	Biomedical Research and Research Training	000	4	4/20/2023	NON-COMPETING CONTINUATION	-$916
														Subtotal = -$916

Issue Date FY: 2020 ( Subtotal = $411,848 )
2020	2020	REGENTS OF THE UNIVERSITY OF MICHIGAN	503 THOMPSON ST	ANN ARBOR	MI	48109	WASHTENAW	USA	Biomedical Research and Research Training	000	4	7/30/2020	NON-COMPETING CONTINUATION	$411,848
														Subtotal = $411,848

Issue Date FY: 2019 ( Subtotal = $596,957 )
2019	2019	REGENTS OF THE UNIVERSITY OF MICHIGAN	503 THOMPSON ST	ANN ARBOR	MI	48109	WASHTENAW	USA	Biomedical Research and Research Training	001	3	9/9/2019	SUPPLEMENT FOR EXPANSION	$185,109
2019	2019	REGENTS OF THE UNIVERSITY OF MICHIGAN	503 THOMPSON ST	ANN ARBOR	MI	48109	WASHTENAW	USA	Biomedical Research and Research Training	000	3	7/15/2019	NON-COMPETING CONTINUATION	$411,848
														Subtotal = $596,957

Issue Date FY: 2018 ( Subtotal = $411,848 )
2018	2018	REGENTS OF THE UNIVERSITY OF MICHIGAN	503 THOMPSON ST	ANN ARBOR	MI	48109	WASHTENAW	USA	Biomedical Research and Research Training	000	2	7/30/2018	NON-COMPETING CONTINUATION	$411,848
														Subtotal = $411,848

Issue Date FY: 2017 ( Subtotal = $409,490 )
2017	2017	REGENTS OF THE UNIVERSITY OF MICHIGAN	503 THOMPSON ST	ANN ARBOR	MI	48109	WASHTENAW	USA	Biomedical Research and Research Training	000	1	9/8/2017	NEW	$409,490
														Subtotal = $409,490

Grand Total All Awards = $3,164,165

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X-chromosome Inactivation Catalyzed by Genes that Escape X-inactivation

Award Number: R01GM124571

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: 09/08/2017

PERIOD OF PERFORMANCE END DATE: 11/30/2027

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