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Neuron. 2014 Jul 2;83(1):122-34. doi: 10.1016/j.neuron.2014.05.039.

Promoter decommissioning by the NuRD chromatin remodeling complex triggers synaptic connectivity in the mammalian brain.

Author information

1
Department of Anatomy and Neurobiology, Washington University in St. Louis School of Medicine, St. Louis, MO 63110, USA; Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA.
2
Department of Ophthalmology, Children's Hospital Boston, Boston, MA 02115, USA.
3
Cutaneous Biology Research Center, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA.
4
Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.
5
Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA.
6
Department of Anatomy and Neurobiology, Washington University in St. Louis School of Medicine, St. Louis, MO 63110, USA; Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA. Electronic address: bonni@wustl.edu.

Abstract

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 in vivo 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 in vivo. 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 in vivo. Finally, in a targeted in vivo 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.

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PMID:
24991957
PMCID:
PMC4266462
DOI:
10.1016/j.neuron.2014.05.039
[Indexed for MEDLINE]
Free PMC Article

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