A Functional Switch of NuRD Chromatin Remodeling Complex Subunits Regulates Mouse Cortical Development.
Histone modifications and chromatin remodeling represent universal mechanisms by which cells adapt their transcriptional response to rapidly changing environmental conditions. Extensive chromatin remodeling takes place during neuronal development, allowing the transition of pluripotent cells into differentiated neurons. Here, we report that the NuRD complex, which couples ATP-dependent chromatin remodeling with histone deacetylase activity, regulates mouse brain development. Subunit exchange of CHDs, the core ATPase subunits of the NuRD complex, is required for distinct aspects of cortical development. Whereas CHD4 promotes the early proliferation of progenitors, CHD5 facilitates neuronal migration and CHD3 ensures proper layer specification. Inhibition of each CHD leads to defects of neuronal differentiation and migration, which cannot be rescued by expressing heterologous CHDs. Finally, we demonstrate that NuRD complexes containing specific CHDs are recruited to regulatory elements and modulate the expression of genes essential for brain development.
MRC Laboratory for Molecular and Cell Biology, University College London, London WC1E 6BT, UK.
Justyna
J
Nitarska
MRC Laboratory for Molecular and Cell Biology, University College London, London WC1E 6BT, UK.
Jacob G
JG
Smith
MRC Laboratory for Molecular and Cell Biology, University College London, London WC1E 6BT, UK.
William T
WT
Sherlock
MRC Laboratory for Molecular and Cell Biology, University College London, London WC1E 6BT, UK.
Michele M G
MM
Hillege
MRC Laboratory for Molecular and Cell Biology, University College London, London WC1E 6BT, UK.
Alexi
A
Nott
Department of Biological Chemistry, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095-1737 USA.
William D
WD
Barshop
Department of Biological Chemistry, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095-1737 USA.
Ajay A
AA
Vashisht
Department of Biological Chemistry, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095-1737 USA.
James A
JA
Wohlschlegel
Lincoln's Inn Fields Laboratory, The Francis Crick Institute, London WC2A 3LY, UK.
Richard
R
Mitter
MRC Laboratory for Molecular and Cell Biology, University College London, London WC1E 6BT, UK. Electronic address: a.riccio@ucl.ac.uk.
Antonella
A
Riccio
D000818:Animals; D002453:Cell Cycle; D002465:Cell Movement; D002540:Cerebral Cortex / Q000196:embryology* / Q000378:metabolism*; D042002:Chromatin Assembly and Disassembly; D017353:Gene Deletion; D018507:Gene Expression Regulation, Developmental; D056245:Mi-2 Nucleosome Remodeling and Deacetylase Complex / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D008831:Microcephaly / Q000473:pathology; D058953:Neural Stem Cells / Q000166:cytology / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics; D021122:Protein Subunits / Q000378:metabolism*
D021122:Protein Subunits; D056245:Mi-2 Nucleosome Remodeling and Deacetylase Complex
CHD proteins; NuRD complex; chromatin remodeling; cortical development; cortical laminar fate specification; epigenetics; mouse brain; neural progenitors; neural radial migration