Thursday, September 18, 2025 9/18/2025

Aberrant chromatin regulatory mechanisms in Down syndrome brain

Award Number: R01HD097088
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: 09/18/2024
PERIOD OF PERFORMANCE END DATE: 08/31/2029

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Aberrant chromatin regulatory mechanisms in Down syndrome brain - PROJECT SUMMARY Down syndrome (DS) is the most common form of autosomal aneuploidy in humans, with an incidence of ~1 in 700 live births, and is characterized by physical growth delays, skeletal abnormalities, neurological deficits and cognitive impairments. Although the genetic cause of DS is full or partial triplication of chromosome 21 (HSA21), triplicated genes on HSA21 do not fully account for the widespread transcriptional dysregulation observed in DS. Given the tremendous amount of variability in the severity and clinical presentation of DS, it has long been believed that epigenetic processes may also contribute importantly to global patterns of transcriptional dysregulation, both during neurodevelopment and in adulthood. However, until recently, our understanding of how chromatin-based mechanisms may contribute to DS-related phenotypes remained limited. During the previous funding periods of this R01, we found that the HSA21-encoded chromatin effector protein, BRWD1, is upregulated in neurons from individuals with DS and in brain of both male and female trisomic mice. We demonstrated that selective copy number restoration of Brwd1 in trisomic animals robustly rescues deficits in hippocampal LTP, gene expression and cognition. We observed that Brwd1 binds tightly to the mammalian BAF chromatin remodeling complex – both neural progenitor (np) BAF during development and neuronal (n) BAF in adulthood – and that increased Brwd1 expression promotes BAF genomic mistargeting. Importantly, Brwd1 renormalization rescues aberrant BAF localization, along with associated changes in chromatin accessibility and gene expression. These findings established BRWD1 as a key epigenomic mediator of normal neurodevelopment and an important contributor to DS-related phenotypes. Although Brwd1 is clearly important for BAF genomic targeting and neural gene expression, the molecular mechanisms through which this targeting is achieved remains unclear, and the primary neural cell-types affected by Brwd1 triplication in DS-like brain have yet to be explored. Also, while DS has largely been assumed to be untreatable due to disrupted in utero development, our recent data suggest that restoring Brwd1 gene activity in early postnatal brain may be sufficient to ameliorate cognitive deficits in adult trisomic mice, yet the molecular underpinnings and/or importance of neurodevelopmental timing of this rescue have yet to be explored. Using a unique combination of biochemical, single-cell omics, genetic and behavioral analyses, we will comprehensively explore: (Aim 1) the biochemical basis through which Brwd1 recruits the BAF complex to neural chromatin via its histone ‘reader’ functions and protein-protein interactions; (Aim 2) the longitudinal and cell-type specific contributions of Brwd1 triplication to BAF genomic targeting, chromatin accessibility and gene expression across multiple brain regions known to be affected in DS; and (Aim 3) the molecular, physiological and behavioral impact of Brwd1 copy number restoration during postnatal periods. These studies will provide valuable insights into the molecular mechanisms of Brwd1 dysregulation in DS-like brain and inform on the possibility of postnatal treatments for this disorder.


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 = $725,919 )
2025	2025	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	1 GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Child Health and Human Development Extramural Research	001	7	8/8/2025	NON-COMPETING CONTINUATION	$725,919
2025	2023	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	1 GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Child Health and Human Development Extramural Research	000	5	2/13/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $725,919

Issue Date FY: 2024 ( Subtotal = $725,919 )
2024	2024	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	1 GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Child Health and Human Development Extramural Research	000	6	9/18/2024	COMPETING CONTINUATION	$725,919
														Subtotal = $725,919

Issue Date FY: 2023 ( Subtotal = $352,984 )
2023	2023	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	ONE GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Child Health and Human Development Extramural Research	000	5	7/10/2023	NON-COMPETING CONTINUATION	$352,984
														Subtotal = $352,984

Issue Date FY: 2022 ( Subtotal = $352,984 )
2022	2022	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	ONE GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Child Health and Human Development Extramural Research	000	4	7/13/2022	NON-COMPETING CONTINUATION	$352,984
														Subtotal = $352,984

Issue Date FY: 2021 ( Subtotal = $352,984 )
2021	2021	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	ONE GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Child Health and Human Development Extramural Research	000	3	6/25/2021	NON-COMPETING CONTINUATION	$352,984
														Subtotal = $352,984

Issue Date FY: 2020 ( Subtotal = $360,188 )
2020	2020	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	ONE GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Child Health and Human Development Extramural Research	000	2	8/10/2020	NON-COMPETING CONTINUATION	$360,188
														Subtotal = $360,188

Issue Date FY: 2019 ( Subtotal = $360,188 )
2019	2019	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	ONE GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Child Health and Human Development Extramural Research	000	1	9/11/2019	NEW	$360,188
														Subtotal = $360,188

Grand Total All Awards = $3,231,166

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Aberrant chromatin regulatory mechanisms in Down syndrome brain

Award Number: R01HD097088

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: 09/18/2024

PERIOD OF PERFORMANCE END DATE: 08/31/2029

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