TBR1 regulates autism risk genes in the developing neocortex
- James H Notwell1,
- Whitney E Heavner1,
- Siavash Fazel Darbandi2,
- Sol Katzman3,
- William L McKenna3,
- Christian F Ortiz-Londono3,
- David Tastad3,
- Matthew J Eckler3,
- John L.R. Rubenstein2,
- Susan K McConnell1,
- Bin Chen3 and
- Gill Bejerano1,4
- 1 Stanford University;
- 2 University of California, San Francisco;
- 3 University of California, Santa Cruz
- ↵* Corresponding author; email: bejerano{at}stanford.edu
Abstract
Exome sequencing studies have identified multiple genes harboring de novo loss-of-function (LoF) variants in individuals with autism spectrum disorders (ASD), including TBR1, a master regulator of cortical development. We performed ChIP-seq for TBR1 during mouse cortical neurogenesis and show that TBR1-bound regions are enriched adjacent to ASD genes. ASD genes were also enriched among genes that are differentially expressed in Tbr1 knockouts, which together with the ChIP-seq data, suggests direct transcriptional regulation. Of the 9 ASD genes examined, 7 were misexpressed in the cortices of Tbr1 knockout mice, including 6 with increased expression in the deep cortical layers. ASD genes with adjacent cortical TBR1 ChIP-seq peaks also showed unusually low levels of LoF mutations in a reference human population and among Icelanders. We then leveraged TBR1 binding to identify an appealing subset of candidate ASD genes. Our findings highlight a TBR1-regulated network of ASD genes in the developing neocortex that are relatively intolerant to LoF mutations, indicating that these genes may play critical roles in normal cortical development.
- Received December 20, 2015.
- Accepted June 17, 2016.
- Published by Cold Spring Harbor Laboratory Press
This article is distributed exclusively by Cold Spring Harbor Laboratory Press for the first six months after the full-issue publication date (see http://genome.cshlp.org/site/misc/terms.xhtml). After six months, it is available under a Creative Commons License (Attribution-NonCommercial 4.0 International), as described at http://creativecommons.org/licenses/by-nc/4.0/.
