Chd7 is indispensable for mammalian brain development through activation of a neuronal differentiation programme.
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.
Division of Molecular Neurogenetics, German Cancer Research Center (DKFZ), DKFZ-ZMBH Alliance, Im Neuenheimer Feld 280, Heidelberg 69120, Germany.
Weijun
W
Feng
Division of Pediatric Neuro-oncology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg 69120, Germany.
Daisuke
D
Kawauchi
Division of Molecular Neurogenetics, German Cancer Research Center (DKFZ), DKFZ-ZMBH Alliance, Im Neuenheimer Feld 280, Heidelberg 69120, Germany.
Huiqin
H
Körkel-Qu
Division of Molecular Neurogenetics, German Cancer Research Center (DKFZ), DKFZ-ZMBH Alliance, Im Neuenheimer Feld 280, Heidelberg 69120, Germany.
Huan
H
Deng
Division of Molecular Neurogenetics, German Cancer Research Center (DKFZ), DKFZ-ZMBH Alliance, Im Neuenheimer Feld 280, Heidelberg 69120, Germany.
Elisabeth
E
Serger
Division of Pediatric Neuro-oncology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg 69120, Germany.
Laura
L
Sieber
Centro Andaluz de Biología Molecular y Medicina Regenerativa (CABIMER), CSIC-Universidad de Sevilla-Universidad Pablo de Olavide, Sevilla 41092, Spain.
Jenna Ariel
JA
Lieberman
Centro Andaluz de Biología Molecular y Medicina Regenerativa (CABIMER), CSIC-Universidad de Sevilla-Universidad Pablo de Olavide, Sevilla 41092, Spain.
Silvia
S
Jimeno-González
Division of Pediatric Neuro-oncology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg 69120, Germany.
Sander
S
Lambo
Molecular Genetics, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg 69120, Germany.
Bola S
BS
Hanna
Division of Molecular Neurogenetics, German Cancer Research Center (DKFZ), DKFZ-ZMBH Alliance, Im Neuenheimer Feld 280, Heidelberg 69120, Germany.
Yassin
Y
Harim
Division of Molecular Neurogenetics, German Cancer Research Center (DKFZ), DKFZ-ZMBH Alliance, Im Neuenheimer Feld 280, Heidelberg 69120, Germany.
Malin
M
Jansen
Division of Molecular Neurogenetics, German Cancer Research Center (DKFZ), DKFZ-ZMBH Alliance, Im Neuenheimer Feld 280, Heidelberg 69120, Germany.
Anna
A
Neuerburg
Division of Molecular Neurogenetics, German Cancer Research Center (DKFZ), DKFZ-ZMBH Alliance, Im Neuenheimer Feld 280, Heidelberg 69120, Germany.
Olga
O
Friesen
Molecular Genetics, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg 69120, Germany.
Marc
M
Zuckermann
Division of Pediatric Neuro-oncology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg 69120, Germany.
Vijayanad
V
Rajendran
Molecular Genetics, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg 69120, Germany.
Jan
0000-0003-0557-679X
J
Gronych
Institut Curie, CNRS UMR 3347, INSERM U1021, Centre Universitaire, Bâtiment 110, 91405 Orsay, France.
Olivier
O
Ayrault
Clinical Cooperation Unit Neuropathology, German Cancer Research Centre (DKFZ), Department of Neuropathology, University of Heidelberg, Heidelberg 69120, Germany.|German Cancer Consortium (DKTK), Core Center Heidelberg, Heidelberg 69120, Germany.
Andrey
A
Korshunov
Division of Pediatric Neuro-oncology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg 69120, Germany.|German Cancer Consortium (DKTK), Core Center Heidelberg, Heidelberg 69120, Germany.
David T W
DT
Jones
Division of Pediatric Neuro-oncology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg 69120, Germany.
Marcel
M
Kool
Department of Developmental Neurobiology, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, Tennessee 38105, USA.
Paul A
PA
Northcott
Molecular Genetics, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg 69120, Germany.|German Cancer Consortium (DKTK), Core Center Heidelberg, Heidelberg 69120, Germany.
Peter
P
Lichter
Centro Andaluz de Biología Molecular y Medicina Regenerativa (CABIMER), CSIC-Universidad de Sevilla-Universidad Pablo de Olavide, Sevilla 41092, Spain.
Felipe
F
Cortés-Ledesma
Division of Pediatric Neuro-oncology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg 69120, Germany.|German Cancer Consortium (DKTK), Core Center Heidelberg, Heidelberg 69120, Germany.|Department of Pediatric Hematology and Oncology, Heidelberg University Hospital, Im Neuenheimer Feld 430, 69120 Heidelberg, Germany.
Stefan M
SM
Pfister
Division of Molecular Neurogenetics, German Cancer Research Center (DKFZ), DKFZ-ZMBH Alliance, Im Neuenheimer Feld 280, Heidelberg 69120, Germany.
Hai-Kun
HK
Liu
D000818:Animals; D001921:Brain / Q000166:cytology / Q000254:growth & development / Q000378:metabolism*; D002454:Cell Differentiation / Q000235:genetics*; D002531:Cerebellum / Q000166:cytology / Q000254:growth & development / Q000378:metabolism; D002843:Chromatin / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D020869:Gene Expression Profiling; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D008322:Mammals / Q000235:genetics / Q000254:growth & development / Q000378:metabolism; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009474:Neurons / Q000166:cytology / Q000378:metabolism*
C507367:Chd7 protein, mouse; D002843:Chromatin; D004268:DNA-Binding Proteins