Journal Article

Loss of the neural-specific BAF subunit ACTL6B relieves repression of early response genes and causes recessive autism

Staahl, Brett T., Crabtree, Gerald R., Baek, Seung Tae, Shipony, Zohar, Walsh, Jessica J., Malenka, Robert C., Gage, Fred H., Marchetto, Maria C. N., Ranish, Jeffrey A., George, Renee D., Son, Esther Y., Ghosh, Shereen, Moncada, Cynthia, Shoji, Hirotaka, Elias, Laura, Sultan, Tipu, Chen, Dillon, Li, Hongjie, Miller, Erik L., Wenderski, Wendy, Linker, Sara B., Krokhotin, Andrey, Gillespie, Mark A., Wang, Lu, Miyakawa, Tsuyoshi, Luo, Liqun, Stanley, Valentina, Gleeson, Joseph G., Zaki, Maha S.

2020

Overview

Synaptic activity in neurons leads to the rapid activation of genes involved in mammalian behavior. ATP-dependent chromatin remodelers such as the BAF complex contribute to these responses and are generally thought to activate transcription. However, the mechanisms keeping such “early activation” genes silent have been a mystery. In the course of investigating Mendelian recessive autism, we identified six families with segregating loss-of-function mutations in the neuronal BAF (nBAF) subunit ACTL6B (originally named BAF53b). Accordingly, ACTL6B was the most significantly mutated gene in the Simons Recessive Autism Cohort. At least 14 subunits of the nBAF complex are mutated in autism, collectively making it a major contributor to autism spectrum disorder (ASD). Patient mutations destabilized ACTL6B protein in neurons and rerouted dendrites to the wrong glomerulus in the fly olfactory system. Humans and mice lacking ACTL6B showed corpus callosum hypoplasia, indicating a conserved role for ACTL6B in facilitating neural connectivity. Actl6b knockout mice on two genetic backgrounds exhibited ASD-related behaviors, including social and memory impairments, repetitive behaviors, and hyperactivity. Surprisingly, mutation of Actl6b relieved repression of early response genes including AP1 transcription factors (Fos, Fosl2, Fosb, and Junb), increased chromatin accessibility at AP1 binding sites, and transcriptional changes in late response genes associated with early response transcription factor activity. ACTL6B loss is thus an important cause of recessive ASD, with impaired neuronspecific chromatin repression indicated as a potential mechanism.

• Publisher: National Academy of Sciences
• Subject: Actins - genetics / Activator protein 1 / Adenosine Triphosphate - genetics / Animals / Autism / Autism Spectrum Disorder - genetics / Autism Spectrum Disorder - pathology / Behavior, Animal - physiology / Binding sites / Biological Sciences / Chromatin / Chromatin - genetics / Chromatin Assembly and Disassembly - genetics / Chromosomal Proteins, Non-Histone - genetics / Chromosome Pairing - genetics / Chromosome Pairing - physiology / Corpus callosum / Corpus Callosum - metabolism / Corpus Callosum - pathology / Dendrites / Dendrites - genetics / Dendrites - physiology / Disease Models, Animal / DNA-Binding Proteins - genetics / FosB protein / Gene Expression Regulation - genetics / Gene silencing / Genes / Glomerulus / Hippocampus - metabolism / Hippocampus - pathology / Humans / Hyperactivity / Hypoplasia / JunB protein / Mice / Mice, Knockout / Mutation / Mutation - genetics / Neural networks / Neurons / Neurons - metabolism / Neurons - pathology / Neuroscience / Olfactory glomeruli / Olfactory system / PNAS Plus / Social behavior / Transcription activation / Transcription factors / Transcription Factors - genetics