TBR1 regulates autism risk genes in the developing neocortex.
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 nine ASD genes examined, seven were misexpressed in the cortices of Tbr1 knockout mice, including six 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.
Department of Computer Science, Stanford University, Stanford, California 94305, USA;
James H
JH
Notwell
Department of Developmental Biology, Stanford University, Stanford, California 94305, USA; Department of Biology, Stanford University, Stanford, California 94305, USA;
Whitney E
WE
Heavner
Department of Psychiatry, University of California, San Francisco, San Francisco, California 94143, USA;
Siavash Fazel
SF
Darbandi
Center for Biomolecular Science and Engineering, University of California, Santa Cruz, Santa Cruz, California 95064, USA;
Sol
S
Katzman
Department of Molecular, Cell, and Developmental Biology, University of California, Santa Cruz, Santa Cruz, California 95064, USA;
William L
WL
McKenna
Department of Molecular, Cell, and Developmental Biology, University of California, Santa Cruz, Santa Cruz, California 95064, USA;
Christian F
CF
Ortiz-Londono
Department of Molecular, Cell, and Developmental Biology, University of California, Santa Cruz, Santa Cruz, California 95064, USA;
David
D
Tastad
Department of Molecular, Cell, and Developmental Biology, University of California, Santa Cruz, Santa Cruz, California 95064, USA;
Matthew J
MJ
Eckler
Department of Psychiatry, University of California, San Francisco, San Francisco, California 94143, USA;
John L R
JL
Rubenstein
Department of Biology, Stanford University, Stanford, California 94305, USA;
Susan K
SK
McConnell
Department of Molecular, Cell, and Developmental Biology, University of California, Santa Cruz, Santa Cruz, California 95064, USA;
Bin
B
Chen
Department of Computer Science, Stanford University, Stanford, California 94305, USA; Department of Developmental Biology, Stanford University, Stanford, California 94305, USA; Division of Medical Genetics, Department of Pediatrics, Stanford University, Stanford, California 94305, USA.
Gill
G
Bejerano
D000818:Animals; D000067877:Autism Spectrum Disorder / Q000235:genetics* / Q000503:physiopathology; D004268:DNA-Binding Proteins / Q000235:genetics*; D004195:Disease Models, Animal; D059472:Exome / Q000235:genetics; D005786:Gene Expression Regulation; D055786:Gene Knockout Techniques; D006801:Humans; D051379:Mice; D009154:Mutation; D019579:Neocortex / Q000254:growth & development / Q000503:physiopathology*; D055495:Neurogenesis / Q000235:genetics*; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D012307:Risk Factors; D020825:T-Box Domain Proteins
D004268:DNA-Binding Proteins; D020825:T-Box Domain Proteins; C492271:Tbr1 protein, mouse