Résumé
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.
| Langue d'origine | English |
|---|---|
| Pages (de-à) | 122-134 |
| Nombre de pages | 13 |
| Journal | Neuron |
| Volume | 83 |
| Numéro de publication | 1 |
| DOI | |
| Statut de publication | Published - juill. 2 2014 |
| Publié à l'externe | Oui |
Note bibliographique
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.
ASJC Scopus Subject Areas
- General Neuroscience