TY - JOUR
T1 - Promoter decommissioning by the NuRD chromatin remodeling complex triggers synaptic connectivity in the mammalian brain
AU - Yamada, Tomoko
AU - Yang, Yue
AU - Hemberg, Martin
AU - Yoshida, Toshimi
AU - Cho, Ha Young
AU - Murphy, J. Patrick
AU - Fioravante, Diasynou
AU - Regehr, Wade G.
AU - Gygi, Steven P.
AU - Georgopoulos, Katia
AU - Bonni, Azad
N1 - Funding Information:
We thank members of the Bonni laboratory for helpful discussions and critical reading of the manuscript. Supported by NIH grant NS041021 (to A.B.), the Mathers Foundation (to A.B.), the Japan Society for the Promotion of Science (to T. Yamada), NIH training grant AG000222 (to Y.Y.), NIH grant NS032405 (to W.G.R.), and NIH training grant NS007484 (to D.F.). We thank the Genome Technology Access Center at Washington University, which is supported by NCI P30 CA91842 to the Siteman Cancer Center and by ICTS/CTSA UL1TR000448.
PY - 2014/7/2
Y1 - 2014/7/2
N2 - Precise control of gene expression plays fundamental roles in brain development, but the roles of chromatin regulators in neuronal connectivity have remained poorly understood. We report that depletion of the NuRD complex by invivo RNAi and conditional knockout of the core NuRD subunit Chd4 profoundly impairs the establishment of granule neuron parallel fiber/Purkinje cell synapses in the rodent cerebellar cortex invivo. By interfacing genome-wide sequencing of transcripts and ChIP-seq analyses, we uncover a network of repressed genes and distinct histone modifications at target gene promoters that are developmentally regulated by the NuRD complex in the cerebellum invivo. Finally, in a targeted invivo RNAi screen of NuRD target genes, we identify a program of NuRD-repressed genes that operate as critical regulators of presynaptic differentiation in the cerebellar cortex. Our findings define NuRD-dependent promoter decommissioning as a developmentally regulated programming mechanism that drives synaptic connectivity in the mammalian brain.
AB - Precise control of gene expression plays fundamental roles in brain development, but the roles of chromatin regulators in neuronal connectivity have remained poorly understood. We report that depletion of the NuRD complex by invivo RNAi and conditional knockout of the core NuRD subunit Chd4 profoundly impairs the establishment of granule neuron parallel fiber/Purkinje cell synapses in the rodent cerebellar cortex invivo. By interfacing genome-wide sequencing of transcripts and ChIP-seq analyses, we uncover a network of repressed genes and distinct histone modifications at target gene promoters that are developmentally regulated by the NuRD complex in the cerebellum invivo. Finally, in a targeted invivo RNAi screen of NuRD target genes, we identify a program of NuRD-repressed genes that operate as critical regulators of presynaptic differentiation in the cerebellar cortex. Our findings define NuRD-dependent promoter decommissioning as a developmentally regulated programming mechanism that drives synaptic connectivity in the mammalian brain.
UR - http://www.scopus.com/inward/record.url?scp=84903588021&partnerID=8YFLogxK
U2 - 10.1016/j.neuron.2014.05.039
DO - 10.1016/j.neuron.2014.05.039
M3 - Article
C2 - 24991957
AN - SCOPUS:84903588021
SN - 0896-6273
VL - 83
SP - 122
EP - 134
JO - Neuron
JF - Neuron
IS - 1
ER -