Kavli Affiliate: John Rubenstein
| Authors: Siavash Fazel Darbandi, Joon Yong An, Kenneth Lim, Nicholas F. Page, Lindsay Liang, Athena Ypsilanti, Eirene Markenscoff-Papadimitriou, Matthew W. State, Alex S Nord, Stephan J. Sanders and John L.R. Rubenstein
| Summary:
SUMMARY 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 TCF4, 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 was highly predictive of brain expressed genes. This signature was observed at 96 out of 102 ASD-associated genes. Co-IP and proximal ligation assays imply physical interactions between five TRs in the developing mouse cortex, suggesting shared binding sites. 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 neurodevelopmental outcomes of haploinsufficient disruption. Competing Interest Statement J.L.R.R. is cofounder and stockholder, and currently on the scientific board, of Neurona, a company studying the potential therapeutic use of interneuron transplantation. S.J.S. receives research funding from BioMarin Pharmaceutical. M.W.S. is a consultant to BlackThorn and ArRett Pharmaceuticals. L.L. is a stockholder and employee of Invitae. All other authors declare no competing interests.