Chd7 is indispensable for mammalian brain development through activation of a neuronal differentiation programme

Weijun Feng, Daisuke Kawauchi (), Huiqin Körkel-Qu, Huan Deng, Elisabeth Serger, Laura Sieber, Jenna Ariel Lieberman, Silvia Jimeno-González, Sander Lambo, Bola S. Hanna, Yassin Harim, Malin Jansen, Anna Neuerburg, Olga Friesen, Marc Zuckermann, Vijayanad Rajendran, Jan Gronych, Olivier Ayrault, Andrey Korshunov, David T. W. Jones, Marcel Kool, Paul A. Northcott, Peter Lichter, Felipe Cortés-Ledesma, Stefan M. Pfister () and Hai-Kun Liu ()
Additional contact information
Weijun Feng: German Cancer Research Center (DKFZ), DKFZ–ZMBH Alliance
Daisuke Kawauchi: German Cancer Research Center (DKFZ)
Huiqin Körkel-Qu: German Cancer Research Center (DKFZ), DKFZ–ZMBH Alliance
Huan Deng: German Cancer Research Center (DKFZ), DKFZ–ZMBH Alliance
Elisabeth Serger: German Cancer Research Center (DKFZ), DKFZ–ZMBH Alliance
Laura Sieber: German Cancer Research Center (DKFZ)
Jenna Ariel Lieberman: Centro Andaluz de Biología Molecular y Medicina Regenerativa (CABIMER), CSIC-Universidad de Sevilla-Universidad Pablo de Olavide
Silvia Jimeno-González: Centro Andaluz de Biología Molecular y Medicina Regenerativa (CABIMER), CSIC-Universidad de Sevilla-Universidad Pablo de Olavide
Sander Lambo: German Cancer Research Center (DKFZ)
Bola S. Hanna: Molecular Genetics, German Cancer Research Center (DKFZ)
Yassin Harim: German Cancer Research Center (DKFZ), DKFZ–ZMBH Alliance
Malin Jansen: German Cancer Research Center (DKFZ), DKFZ–ZMBH Alliance
Anna Neuerburg: German Cancer Research Center (DKFZ), DKFZ–ZMBH Alliance
Olga Friesen: German Cancer Research Center (DKFZ), DKFZ–ZMBH Alliance
Marc Zuckermann: Molecular Genetics, German Cancer Research Center (DKFZ)
Vijayanad Rajendran: German Cancer Research Center (DKFZ)
Jan Gronych: Molecular Genetics, German Cancer Research Center (DKFZ)
Olivier Ayrault: Institut Curie, CNRS UMR 3347, INSERM U1021, Centre Universitaire
Andrey Korshunov: Clinical Cooperation Unit Neuropathology, German Cancer Research Centre (DKFZ), University of Heidelberg
David T. W. Jones: German Cancer Research Center (DKFZ)
Marcel Kool: German Cancer Research Center (DKFZ)
Paul A. Northcott: St. Jude Children’s Research Hospital
Peter Lichter: Molecular Genetics, German Cancer Research Center (DKFZ)
Felipe Cortés-Ledesma: Centro Andaluz de Biología Molecular y Medicina Regenerativa (CABIMER), CSIC-Universidad de Sevilla-Universidad Pablo de Olavide
Stefan M. Pfister: German Cancer Research Center (DKFZ)
Hai-Kun Liu: German Cancer Research Center (DKFZ), DKFZ–ZMBH Alliance

Nature Communications, 2017, vol. 8, issue 1, 1-14

Abstract: Abstract Mutations in chromatin modifier genes are frequently associated with neurodevelopmental diseases. We herein demonstrate that the chromodomain helicase DNA-binding protein 7 (Chd7), frequently associated with CHARGE syndrome, is indispensable for normal cerebellar development. Genetic inactivation of Chd7 in cerebellar granule neuron progenitors leads to cerebellar hypoplasia in mice, due to the impairment of granule neuron differentiation, induction of apoptosis and abnormal localization of Purkinje cells, which closely recapitulates known clinical features in the cerebella of CHARGE patients. Combinatory molecular analyses reveal that Chd7 is required for the maintenance of open chromatin and thus activation of genes essential for granule neuron differentiation. We further demonstrate that both Chd7 and Top2b are necessary for the transcription of a set of long neuronal genes in cerebellar granule neurons. Altogether, our comprehensive analyses reveal a mechanism with chromatin remodellers governing brain development via controlling a core transcriptional programme for cell-specific differentiation.

Date: 2017
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DOI: 10.1038/ncomms14758

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