Pleiotropy of autism-associated chromatin regulators.

Autor:	Lasser M; Department of Psychiatry and Behavioral Sciences, University of California, San Francisco, San Francisco, CA 94143, USA.; Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA 94143, USA., Sun N; Department of Psychiatry and Behavioral Sciences, University of California, San Francisco, San Francisco, CA 94143, USA.; Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA 94143, USA., Xu Y; Department of Psychiatry and Behavioral Sciences, University of California, San Francisco, San Francisco, CA 94143, USA.; Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA 94143, USA., Wang S; Department of Psychiatry and Behavioral Sciences, University of California, San Francisco, San Francisco, CA 94143, USA.; Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA 94143, USA., Drake S; Department of Psychiatry and Behavioral Sciences, University of California, San Francisco, San Francisco, CA 94143, USA.; Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA 94143, USA., Law K; Department of Psychiatry and Behavioral Sciences, University of California, San Francisco, San Francisco, CA 94143, USA.; Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA 94143, USA., Gonzalez S; Department of Psychiatry and Behavioral Sciences, University of California, San Francisco, San Francisco, CA 94143, USA.; Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA 94143, USA., Wang B; Department of Psychiatry and Behavioral Sciences, University of California, San Francisco, San Francisco, CA 94143, USA.; Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA 94143, USA.; Langley Porter Psychiatric Institute, University of California, San Francisco, San Francisco, CA 94143, USA., Drury V; Department of Psychiatry and Behavioral Sciences, University of California, San Francisco, San Francisco, CA 94143, USA.; Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA 94143, USA., Castillo O; Department of Psychiatry and Behavioral Sciences, University of California, San Francisco, San Francisco, CA 94143, USA.; Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA 94143, USA., Zaltsman Y; Department of Psychiatry and Behavioral Sciences, University of California, San Francisco, San Francisco, CA 94143, USA.; Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA 94143, USA., Dea J; Department of Psychiatry and Behavioral Sciences, University of California, San Francisco, San Francisco, CA 94143, USA.; Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA 94143, USA., Bader E; Department of Psychiatry and Behavioral Sciences, University of California, San Francisco, San Francisco, CA 94143, USA.; Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA 94143, USA., McCluskey KE; Department of Psychiatry and Behavioral Sciences, University of California, San Francisco, San Francisco, CA 94143, USA.; Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA 94143, USA., State MW; Department of Psychiatry and Behavioral Sciences, University of California, San Francisco, San Francisco, CA 94143, USA.; Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA 94143, USA.; Langley Porter Psychiatric Institute, University of California, San Francisco, San Francisco, CA 94143, USA.; Quantitative Biosciences Institute, University of California, San Francisco, San Francisco, CA 94143, USA., Willsey AJ; Department of Psychiatry and Behavioral Sciences, University of California, San Francisco, San Francisco, CA 94143, USA.; Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA 94143, USA.; Quantitative Biosciences Institute, University of California, San Francisco, San Francisco, CA 94143, USA., Willsey HR; Department of Psychiatry and Behavioral Sciences, University of California, San Francisco, San Francisco, CA 94143, USA.; Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA 94143, USA.; Chan Zuckerberg Biohub - San Francisco, San Francisco, CA 94158, USA.
Jazyk:	angličtina
Zdroj:	Development (Cambridge, England) [Development] 2023 Jul 15; Vol. 150 (14). Date of Electronic Publication: 2023 Jul 18.
DOI:	10.1242/dev.201515
Abstrakt:	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. Competing Interests: Competing interests The authors declare no competing or financial interests. (© 2023. Published by The Company of Biologists Ltd.)
Databáze:	MEDLINE
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