Autism-associated transcriptional regulators target shared loci proximal to brain-expressed genes.

Fazel Darbandi, S.; An, J. Y.; Lim, K.; Page, N. F.; Liang, L.; Ypsilanti, A.; Markenscoff-Papadimitriou, E.; State, M. W.; Nord, A. S.; Sanders, S. J.; Rubenstein, J. L. R.

doi:10.1101/2022.10.17.512583

bioRxiv · 10.1101/2022.10.17.512583

Autism-associated transcriptional regulators target shared loci proximal to brain-expressed genes.

Fazel Darbandi, S.·An, J. Y.·Lim, K.·Page, N. F.·Liang, L.·Ypsilanti, A.·Markenscoff-Papadimitriou, E.·State, M. W.·Nord, A. S.·Sanders, S. J.·Rubenstein, J. L. R.

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Abstract

Many autism spectrum disorder (ASD)-associated genes act as transcriptional regulators (TRs). ChIP-seq was used to identify the regulatory targets of ARID1B, BCL11A, FOXP1, TBR1, and TCF7L2, ASD-associated TRs in the developing human and mouse cortex. These TRs shared substantial overlap in the binding sites, especially within open chromatin. The overlap within a promoter region, 1-2,000bp upstream of transcription start site, was highly predictive of brain expressed genes. This signature was observed at 96 out of 102 ASD-associated genes. In vitro CRISPRi against ARID1B and TBR1 delineated downstream convergent biology in mouse cortical cultures. After eight days, NeuN+ and CALB+ cells were decreased, GFAP+ cells were increased, and transcriptomic signatures correlated with the postmortem brain samples from individuals with ASD. We suggest functional convergence across five ASD-associated TRs leads to shared neurodevelopmental outcomes of haploinsufficient disruption.

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Fazel Darbandi, S., An, J. Y., Lim, K., Page, N. F., Liang, L., Ypsilanti, A., Markenscoff-Papadimitriou, E., State, M. W., Nord, A. S., Sanders, S. J., Rubenstein, J. L. R.. 2022-10-18. Autism-associated transcriptional regulators target shared loci proximal to brain-expressed genes.. https://doi.org/10.1101/2022.10.17.512583

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