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MECHANISMS OF EPIGENETIC REGULATION IN NERVOUS SYSTEM DEVELOPMENT

Award Number: R01MH117405
ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 03/14/2019
PERIOD OF PERFORMANCE END DATE: 11/30/2028

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MECHANISMS OF EPIGENETIC REGULATION IN NERVOUS SYSTEM DEVELOPMENT - PROJECT SUMMARY With the identification of hundreds of genes associated with autism spectrum and related neurodevelopmental disorders (ASD/NDD), there is a pressing need to define the molecular pathways these genes contribute to in the nervous system and to dissect how their disruption alters brain function to drive disease. Methylation of cytosines in DNA classically occurs at CG dinucleotides in mammalian cells, serving as an epigenetic mark often associated with gene repression. However, a unique form of non-CG DNA methylation that occurs primarily at CA dinucleotides (mCA) is highly enriched in neurons and has emerged as an essential regulatory modification needed to tune neuronal transcriptomes. Notably, this DNA mark is susceptible to disruption due to mutation of the ASD/NDD gene DNMT3A, as well as the Rett syndrome methyl-DNA-binding protein MeCP2, suggesting that the specialized neuronal DNA methylation pathway may be vulnerable to disruption across additional causes of ASD/NDD. In recent studies, we have uncovered new mechanisms that govern the patterning of mCA in neurons and identified key functional outputs for the neuronal DNA methylation pathway in regulating cell-type-specific transcriptomes. We have shown that the histone H3 lysine 36 dimethyl mark (H3K36me2) is necessary for targeting DNMT3A to deposit mCA and demonstrated that mutation of the ASD/NDD-associated gene, NSD1, disrupts this histone mark, leading to altered neuronal DNA methylation. We have further uncovered evidence that mCA deposited by the NSD1- H3K36me2-DNMT3A cascade is read out by MeCP2 in a cell-type specific manner to control expression of genes that define neuronal subtype-specific transcriptomes. In our proposed studies we will build on these findings to investigate the mechanisms of DNMT3A targeting by H3K36me2 and assess their potential disruption due to additional genetic lesions in ASD/NDD (Aim 1). We will then dissect the cell-type specific epigenetic consequences of perturbing the NSD1-H3K36me2-DNMT3A cascade in NSD1 mutant mice (Aim 2). Finally, we will employ cutting- edge spatial transcriptomic technologies to probe gene dysregulation caused by mutations in the neuronal DNA methylation pathway across more than a hundred subtypes of neuronal and non-neuronal cells with single-cell spatial resolution (Aim 3). Together these studies are significant because they will define new roles for ASD/NDD-associated factors in the neuronal DNA methylation pathway and explore how disruption of these factors can alter neuronal function. Furthermore, our implementation of spatial transcriptomic analysis for the study of ASD/NDD will provide systematic understanding of the transcriptomic impacts caused by disease-associated mutations in this pathway at the highest level of resolution.


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 = $556,920 )
2025	2025	WASHINGTON UNIVERSITY, THE	1 BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Mental Health Research Grants	000	7	11/5/2024	NON-COMPETING CONTINUATION	$556,920
2025	2024	WASHINGTON UNIVERSITY, THE	1 BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Mental Health Research Grants	002	6	2/21/2025	COMPETING CONTINUATION	$6,039
2025	2023	WASHINGTON UNIVERSITY, THE	1 BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Mental Health Research Grants	001	5	2/21/2025	NON-COMPETING CONTINUATION	-$6,039
														Subtotal = $556,920

Issue Date FY: 2024 ( Subtotal = $655,201 )
2024	2024	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63110	SAINT LOUIS CITY	USA	Mental Health Research Grants	001	6	5/1/2024	COMPETING CONTINUATION	$65,519
2024	2024	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63110	SAINT LOUIS CITY	USA	Mental Health Research Grants	000	6	11/24/2023	COMPETING CONTINUATION	$589,682
														Subtotal = $655,201

Issue Date FY: 2023 ( Subtotal = $393,750 )
2023	2023	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Mental Health Research Grants	000	5	1/18/2023	NON-COMPETING CONTINUATION	$393,750
														Subtotal = $393,750

Issue Date FY: 2022 ( Subtotal = $393,750 )
2022	2022	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Mental Health Research Grants	001	4	5/16/2022	NON-COMPETING CONTINUATION	$39,375
2022	2022	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Mental Health Research Grants	000	4	1/26/2022	NON-COMPETING CONTINUATION	$354,375
														Subtotal = $393,750

Issue Date FY: 2021 ( Subtotal = $393,750 )
2021	2021	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Mental Health Research Grants	000	3	2/1/2021	NON-COMPETING CONTINUATION	$393,750
														Subtotal = $393,750

Issue Date FY: 2020 ( Subtotal = $393,229 )
2020	2020	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Mental Health Research Grants	000	2	2/10/2020	NON-COMPETING CONTINUATION	$393,229
														Subtotal = $393,229

Issue Date FY: 2019 ( Subtotal = $391,250 )
2019	2019	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Mental Health Research Grants	000	1	3/14/2019	NEW	$391,250
														Subtotal = $391,250

Grand Total All Awards = $3,177,850

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MECHANISMS OF EPIGENETIC REGULATION IN NERVOUS SYSTEM DEVELOPMENT

Award Number: R01MH117405

ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 03/14/2019

PERIOD OF PERFORMANCE END DATE: 11/30/2028

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