CRISPR tiling deletion screens reveal functional enhancers of neuropsychiatric risk genes and allelic compensation effects (ACE) on transcription.

Autor:	Ren X; Institute for Human Genetics, University of California, San Francisco, San Francisco, CA, USA., Zheng L; Bioinformatics and Systems Biology Graduate Program, University of California, San Diego, La Jolla, CA, USA., Maliskova L; Institute for Human Genetics, University of California, San Francisco, San Francisco, CA, USA., Tam TW; Institute for Human Genetics, University of California, San Francisco, San Francisco, CA, USA., Sun Y; Institute for Human Genetics, University of California, San Francisco, San Francisco, CA, USA., Liu H; Institute for Human Genetics, University of California, San Francisco, San Francisco, CA, USA., Lee J; Institute for Human Genetics, University of California, San Francisco, San Francisco, CA, USA., Takagi MA; Institute for Human Genetics, University of California, San Francisco, San Francisco, CA, USA., Li B; Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA, USA., Ren B; Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA, USA.; Center for Epigenomics, University of California, San Diego, La Jolla, CA, USA.; Moores Cancer Center, University of California, San Diego, La Jolla, CA, USA., Wang W; Bioinformatics and Systems Biology Graduate Program, University of California, San Diego, La Jolla, CA, USA.; Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA, USA.; Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, CA, USA., Shen Y; Institute for Human Genetics, University of California, San Francisco, San Francisco, CA, USA.; Department of Neurology, University of California, San Francisco, San Francisco, CA, USA.; Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA, USA.
Jazyk:	angličtina
Zdroj:	BioRxiv : the preprint server for biology [bioRxiv] 2024 Oct 10. Date of Electronic Publication: 2024 Oct 10.
DOI:	10.1101/2024.10.08.616922
Abstrakt:	Precise transcriptional regulation is critical for cellular function and development, yet the mechanism of this process remains poorly understood for many genes. To gain a deeper understanding of the regulation of neuropsychiatric disease risk genes, we identified a total of 39 functional enhancers for four dosage-sensitive genes, APP , FMR1 , MECP2 , and SIN3A , using CRISPR tiling deletion screening in human induced pluripotent stem cell (iPSC)-induced excitatory neurons. We found that enhancer annotation provides potential pathological insights into disease-associated copy number variants. More importantly, we discovered that allelic enhancer deletions at SIN3A could be compensated by increased transcriptional activities from the other intact allele. Such allelic compensation effects (ACE) on transcription is stably maintained during differentiation and, once established, cannot be reversed by ectopic SIN3A expression. Further, ACE at SIN3A occurs through dosage sensing by the promoter. Together, our findings unravel a regulatory compensation mechanism that ensures stable and precise transcriptional output for SIN3A , and potentially other dosage-sensitive genes. Competing Interests: Competing interests B.R. is a co-founder and consultant of Arima Genomics Inc. and co-founder of Epigenome Technologies. The other authors declare that they have no competing interests.
Databáze:	MEDLINE
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