# Role of histone ubiquitination in neurodevelopment and disease > **NIH NIH R01** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2022 · $390,637 ## Abstract 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. ## Key facts - **NIH application ID:** 10318586 - **Project number:** 5R01NS101597-05 - **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR - **Principal Investigator:** Stephanie Lee Bielas - **Activity code:** R01 (R01, R21, SBIR, etc.) - **Funding institute:** NIH - **Fiscal year:** 2022 - **Award amount:** $390,637 - **Award type:** 5 - **Project period:** 2017-12-15 → 2022-11-30 ## Primary source NIH RePORTER: https://reporter.nih.gov/project-details/10318586 ## Citation > US National Institutes of Health, RePORTER application 10318586, Role of histone ubiquitination in neurodevelopment and disease (5R01NS101597-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10318586. Licensed CC0. --- *[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*