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Development 2023 Jul 15;15014:. doi: 10.1242/dev.201515.
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Pleiotropy of autism-associated chromatin regulators.

Lasser M , Sun N , Xu Y , Wang S , Drake S , Law K , Gonzalez S , Wang B , Drury V , Castillo O , Zaltsman Y , Dea J , Bader E , McCluskey KE , State MW , Willsey AJ , Willsey HR .

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.

PubMed ID: 37366052
PMC ID: PMC10399978
Article link: Development
Grant support: [+]

Species referenced: Xenopus tropicalis Xenopus laevis
Genes referenced: adnp arid1b celf1 chd2 chd3 chd8 crebbp csnk1e ctnnb1 cul3 cyld deaf1 fam120a gigyf1 itsn1 KIAA0232 kmt5b med23 phldb1 pogz ralgapb satb2 scaper stab2 strip1 taf4 tbl1xr1 tcf20 tnrc6b tsc1 ubr5 wac
GO keywords: microtubule [+]
Antibodies: Casp3 Ab1 H2afx Ab2

Disease Ontology terms: autism spectrum disorder

Article Images: [+] show captions
References [+] :
Adhya, Atypical Neurogenesis in Induced Pluripotent Stem Cells From Autistic Individuals. 2021, Pubmed