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RINGs, DUBs and Abnormal Brain Growth—Histone H2A Ubiquitination in Brain Development and Disease

During mammalian neurodevelopment, signaling pathways converge upon transcription factors (TFs) to establish appropriate gene expression programmes leading to the production of distinct neural and glial cell types. This process is partially regulated by the dynamic modulation of chromatin states by...

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Autores principales: Doyle, Lucy Anne, Unlu Bektas, Firuze, Chatzantonaki, Eleftheria, Repton, Charlotte, Derrien, Alexandra, Illingworth, Robert Scott
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9778336/
https://www.ncbi.nlm.nih.gov/pubmed/36547251
http://dx.doi.org/10.3390/epigenomes6040042
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author Doyle, Lucy Anne
Unlu Bektas, Firuze
Chatzantonaki, Eleftheria
Repton, Charlotte
Derrien, Alexandra
Illingworth, Robert Scott
author_facet Doyle, Lucy Anne
Unlu Bektas, Firuze
Chatzantonaki, Eleftheria
Repton, Charlotte
Derrien, Alexandra
Illingworth, Robert Scott
author_sort Doyle, Lucy Anne
collection PubMed
description During mammalian neurodevelopment, signaling pathways converge upon transcription factors (TFs) to establish appropriate gene expression programmes leading to the production of distinct neural and glial cell types. This process is partially regulated by the dynamic modulation of chromatin states by epigenetic systems, including the polycomb group (PcG) family of co-repressors. PcG proteins form multi-subunit assemblies that sub-divide into distinct, yet functionally related families. Polycomb repressive complexes 1 and 2 (PRC1 and 2) modify the chemical properties of chromatin by covalently modifying histone tails via H2A ubiquitination (H2AK119ub1) and H3 methylation, respectively. In contrast to the PRCs, the Polycomb repressive deubiquitinase (PR-DUB) complex removes H2AK119ub1 from chromatin through the action of the C-terminal hydrolase BAP1. Genetic screening has identified several PcG mutations that are causally associated with a range of congenital neuropathologies associated with both localised and/or systemic growth abnormalities. As PRC1 and PR-DUB hold opposing functions to control H2AK119ub1 levels across the genome, it is plausible that such neurodevelopmental disorders arise through a common mechanism. In this review, we will focus on advancements regarding the composition and opposing molecular functions of mammalian PRC1 and PR-DUB, and explore how their dysfunction contributes to the emergence of neurodevelopmental disorders.
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spelling pubmed-97783362022-12-23 RINGs, DUBs and Abnormal Brain Growth—Histone H2A Ubiquitination in Brain Development and Disease Doyle, Lucy Anne Unlu Bektas, Firuze Chatzantonaki, Eleftheria Repton, Charlotte Derrien, Alexandra Illingworth, Robert Scott Epigenomes Review During mammalian neurodevelopment, signaling pathways converge upon transcription factors (TFs) to establish appropriate gene expression programmes leading to the production of distinct neural and glial cell types. This process is partially regulated by the dynamic modulation of chromatin states by epigenetic systems, including the polycomb group (PcG) family of co-repressors. PcG proteins form multi-subunit assemblies that sub-divide into distinct, yet functionally related families. Polycomb repressive complexes 1 and 2 (PRC1 and 2) modify the chemical properties of chromatin by covalently modifying histone tails via H2A ubiquitination (H2AK119ub1) and H3 methylation, respectively. In contrast to the PRCs, the Polycomb repressive deubiquitinase (PR-DUB) complex removes H2AK119ub1 from chromatin through the action of the C-terminal hydrolase BAP1. Genetic screening has identified several PcG mutations that are causally associated with a range of congenital neuropathologies associated with both localised and/or systemic growth abnormalities. As PRC1 and PR-DUB hold opposing functions to control H2AK119ub1 levels across the genome, it is plausible that such neurodevelopmental disorders arise through a common mechanism. In this review, we will focus on advancements regarding the composition and opposing molecular functions of mammalian PRC1 and PR-DUB, and explore how their dysfunction contributes to the emergence of neurodevelopmental disorders. MDPI 2022-12-02 /pmc/articles/PMC9778336/ /pubmed/36547251 http://dx.doi.org/10.3390/epigenomes6040042 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Review
Doyle, Lucy Anne
Unlu Bektas, Firuze
Chatzantonaki, Eleftheria
Repton, Charlotte
Derrien, Alexandra
Illingworth, Robert Scott
RINGs, DUBs and Abnormal Brain Growth—Histone H2A Ubiquitination in Brain Development and Disease
title RINGs, DUBs and Abnormal Brain Growth—Histone H2A Ubiquitination in Brain Development and Disease
title_full RINGs, DUBs and Abnormal Brain Growth—Histone H2A Ubiquitination in Brain Development and Disease
title_fullStr RINGs, DUBs and Abnormal Brain Growth—Histone H2A Ubiquitination in Brain Development and Disease
title_full_unstemmed RINGs, DUBs and Abnormal Brain Growth—Histone H2A Ubiquitination in Brain Development and Disease
title_short RINGs, DUBs and Abnormal Brain Growth—Histone H2A Ubiquitination in Brain Development and Disease
title_sort rings, dubs and abnormal brain growth—histone h2a ubiquitination in brain development and disease
topic Review
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9778336/
https://www.ncbi.nlm.nih.gov/pubmed/36547251
http://dx.doi.org/10.3390/epigenomes6040042
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