TY - JOUR
T1 - Loss of the neural-specific BAF subunit ACTL6B relieves repression of early response genes and causes recessive autism
AU - Wenderski, Wendy
AU - Wang, Lu
AU - Krokhotin, Andrey
AU - Walsh, Jessica J.
AU - Li, Hongjie
AU - Shoji, Hirotaka
AU - Ghosh, Shereen
AU - George, Renee D.
AU - Miller, Erik L.
AU - Elias, Laura
AU - Gillespie, Mark A.
AU - Son, Esther Y.
AU - Staahl, Brett T.
AU - Baek, Seung Tae
AU - Stanley, Valentina
AU - Moncada, Cynthia
AU - Shipony, Zohar
AU - Linker, Sara B.
AU - Marchetto, Maria C.N.
AU - Gage, Fred H.
AU - Chen, Dillon
AU - Sultan, Tipu
AU - Zaki, Maha S.
AU - Ranish, Jeffrey A.
AU - Miyakawa, Tsuyoshi
AU - Luo, Liqun
AU - Malenka, Robert C.
AU - Crabtree, Gerald R.
AU - Gleeson, Joseph G.
N1 - Funding Information:
ACKNOWLEDGMENTS. We thank Lei Chen, Alex Valdefiera, and Claire M. Ellis for their help with mouse breeding. We thank Kyle Loh, Lay Teng Ang, Alon Goren, and Ian Maze for thoughtful discussion. This work was supported by Simons Foundation for Autism Research Grant 514863 (to J.G.G. and G.R.C.); National Institutes of Health Grant NS046789 (to G.R.C.); Grant R01NS048453 and Qatar National Research Fund National Priorities Research Program Grant 6-1463-3-351 (to J.G.G. and T.B.-O.); Grants 1F31MH116588-01 and 2T32GM007790-38 (to W.W.); Grant 5T32GM008666 (to S.G.); and Grants U54HG003067 (to the Broad Institute) and U54HG006504 (to the Yale Center for Mendelian Disorders). Behavior studies were supported by grants from the Wu Tsai Neurosciences Institute and NIH P50 DA042012 (to R.C.M. and J.J.W.) and by the Joint Usage/Research Center for Genes, Brain and Behavior (Institute for Comprehensive Medical Science, Fujita Health University) accredited by the Ministry of Education, Culture, Sports, Science and Technology of Japan (to H.S. and T.M.). J.G.G., G.R.C., and L.L. are investigators with the Howard Hughes Medical Institute. J.G.G. received support from Rady Children’s Institute for Genomic Medicine.
Publisher Copyright:
© 2020 National Academy of Sciences. All rights reserved.
PY - 2020/5/5
Y1 - 2020/5/5
N2 - 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.
AB - 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.
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U2 - 10.1073/pnas.1908238117
DO - 10.1073/pnas.1908238117
M3 - Article
C2 - 32312822
AN - SCOPUS:85085094560
VL - 117
SP - 10055
EP - 10066
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
SN - 0027-8424
IS - 18
ER -