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Role of histone ubiquitination in neurodevelopment and disease

Award Number: R01NS101597
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 12/15/2017
PERIOD OF PERFORMANCE END DATE: 11/30/2022

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Role of histone ubiquitination in neurodevelopment and disease - During cortical development, neural progenitor cells (NPCs) produce mature neuronal subtypes in a defined temporal order. Restriction of NPC multipotency determines the cortical neuron composition of the six-layer cortex and is governed by changes to NPC chromatin. Abnormal production of cortical progeny underlies the pathology of neurodevelopmental disorders with features of autism. Chromatin remodeling genes are often identified in autism spectrum disorder (ASD), therefore, neuronal epigenetic mechanisms are likely to be essential for corticogenesis. Developmental remodeling of histone modifications across the chromatin landscape permits spatial and temporal regulation of transcription circuitry that restricts NPC multipotency. One chromatin modification is histone H2A lysine 119 mono-ubiquitination (H2AUb1), an evolutionarily conserved repressive histone modification of the Polycomb group (PcG) proteins. We recently identified human de novo dominant pathogenic variants in the PcG protein ASXL3 (Additional sex comb-like 3) as the genetic basis of neurodevelopmental disorders with syndromic features of autism and intellectual disability. ASXL3 clearly plays a central role in mammalian brain function. We propose experiments to delineate mechanisms of ASXL3 regulation in corticogenesis. We have shown that ASXL3 is a component of the Polycomb repressive deubiquitinase complex (PR-DUB), which deubiqutinates H2AUb1. Pathogenic human ASXL3 variants alter the genome-wide H2AUb1 levels and affect transcriptional regulation in patient-derived cells. We have confirmed and extended this finding in mouse and human neural progenitor cells (NPCs). Although H2AUb1 was described more than three decades ago, its functions in transcriptional regulation and epigenetic repression are less well understood than other histone modifications. We hypothesize that ASXL3-dependent deubiquitination activity plays a critical role in specifying NPC transcriptional programs that contribute to the neuronal diversity of the cortex, and, ultimately, higher brain function. We will define the cortical developmental mechanisms regulated by ASXL3 and H2AUb1 by: (Aim 1) using an existing Asxl3 mutant mice, (Aim 2) determining the genome-wide distribution of excess H2AUb1 in NPCs and the epigenomic mechanisms of corticogenesis using genetically- engineered mice, and (Aim 3) testing the conservation of ASXL3 pathology and PR-DUB activity in human cerebral organoid models of neural development. Our experimental strategy will establish the epigenetic foundation of cortical development, identify paradigms for cortical neurogenesis in NPCs, and, ultimately, unveil the mechanisms of dysregulation that leads to ASD pathology.


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: 2023 ( Subtotal = $0 )
2023	2022	REGENTS OF THE UNIVERSITY OF MICHIGAN	1109 GEDDES AVE, SUITE 3300	ANN ARBOR	MI	48109	WASHTENAW	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	9/25/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $390,637 )
2022	2022	REGENTS OF THE UNIVERSITY OF MICHIGAN	503 THOMPSON ST	ANN ARBOR	MI	48109	WASHTENAW	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	12/8/2021	NON-COMPETING CONTINUATION	$351,572
2022	2022	REGENTS OF THE UNIVERSITY OF MICHIGAN	503 THOMPSON ST	ANN ARBOR	MI	48109	WASHTENAW	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	5	3/28/2022	NON-COMPETING CONTINUATION	$39,065
														Subtotal = $390,637

Issue Date FY: 2021 ( Subtotal = $390,637 )
2021	2021	REGENTS OF THE UNIVERSITY OF MICHIGAN	503 THOMPSON ST	ANN ARBOR	MI	48109	WASHTENAW	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	12/14/2020	NON-COMPETING CONTINUATION	$351,572
2021	2021	REGENTS OF THE UNIVERSITY OF MICHIGAN	503 THOMPSON ST	ANN ARBOR	MI	48109	WASHTENAW	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	4	2/5/2021	NON-COMPETING CONTINUATION	$39,065
														Subtotal = $390,637

Issue Date FY: 2020 ( Subtotal = $390,637 )
2020	2020	REGENTS OF THE UNIVERSITY OF MICHIGAN	503 THOMPSON ST	ANN ARBOR	MI	48109	WASHTENAW	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	3	2/10/2020	NON-COMPETING CONTINUATION	$39,065
2020	2020	REGENTS OF THE UNIVERSITY OF MICHIGAN	503 THOMPSON ST	ANN ARBOR	MI	48109	WASHTENAW	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	11/28/2019	NON-COMPETING CONTINUATION	$351,572
														Subtotal = $390,637

Issue Date FY: 2019 ( Subtotal = $417,126 )
2019	2019	REGENTS OF THE UNIVERSITY OF MICHIGAN	503 THOMPSON ST	ANN ARBOR	MI	48109	WASHTENAW	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	12/24/2018	NON-COMPETING CONTINUATION	$417,126
														Subtotal = $417,126

Issue Date FY: 2018 ( Subtotal = $415,708 )
2018	2018	REGENTS OF THE UNIVERSITY OF MICHIGAN	503 THOMPSON ST	ANN ARBOR	MI	48109	WASHTENAW	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	12/12/2017	NEW	$415,708
														Subtotal = $415,708

Grand Total All Awards = $2,004,745

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Role of histone ubiquitination in neurodevelopment and disease

Award Number: R01NS101597

ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 12/15/2017

PERIOD OF PERFORMANCE END DATE: 11/30/2022

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