Pleiotropy of autism-associated chromatin regulators.
Xenopus
Autism spectrum disorder
Cell cycle
Chromatin
Cilia
Human
Microtubules
Spindles
Tubulin
Journal
Development (Cambridge, England)
ISSN: 1477-9129
Titre abrégé: Development
Pays: England
ID NLM: 8701744
Informations de publication
Date de publication:
15 07 2023
15 07 2023
Historique:
received:
07
12
2022
accepted:
19
06
2023
medline:
19
7
2023
pubmed:
27
6
2023
entrez:
27
6
2023
Statut:
ppublish
Résumé
Gene ontology analyses of high-confidence autism spectrum disorder (ASD) risk genes highlight chromatin regulation and synaptic function as major contributors to pathobiology. Our recent functional work in vivo has additionally implicated tubulin biology and cellular proliferation. As many chromatin regulators, including the ASD risk genes ADNP and CHD3, are known to directly regulate both tubulins and histones, we studied the five chromatin regulators most strongly associated with ASD (ADNP, CHD8, CHD2, POGZ and KMT5B) specifically with respect to tubulin biology. We observe that all five localize to microtubules of the mitotic spindle in vitro in human cells and in vivo in Xenopus. Investigation of CHD2 provides evidence that mutations present in individuals with ASD cause a range of microtubule-related phenotypes, including disrupted localization of the protein at mitotic spindles, cell cycle stalling, DNA damage and cell death. Lastly, we observe that ASD genetic risk is significantly enriched among tubulin-associated proteins, suggesting broader relevance. Together, these results provide additional evidence that the role of tubulin biology and cellular proliferation in ASD warrants further investigation and highlight the pitfalls of relying solely on annotated gene functions in the search for pathological mechanisms.
Identifiants
pubmed: 37366052
pii: 324019
doi: 10.1242/dev.201515
pmc: PMC10399978
pii:
doi:
Substances chimiques
Chromatin
0
Tubulin
0
Histones
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : NIMH NIH HHS
ID : U01 MH115747
Pays : United States
Organisme : NIMH NIH HHS
ID : U01 MH116487
Pays : United States
Informations de copyright
© 2023. Published by The Company of Biologists Ltd.
Déclaration de conflit d'intérêts
Competing interests The authors declare no competing or financial interests.
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