title: Promoter decommissioning by the NuRD chromatin remodeling complex triggers synaptic connectivity in the mammalian brain.
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.
authors.affiliation: 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.
authors.forename: Tomoko
authors.initials: T
authors.lastname: Yamada
authors.affiliation: 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.
authors.forename: Yue
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Department of Ophthalmology, Children's Hospital Boston, Boston, MA 02115, USA.
authors.forename: Martin
authors.initials: M
authors.lastname: Hemberg
authors.affiliation: Cutaneous Biology Research Center, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA.
authors.forename: Toshimi
authors.initials: T
authors.lastname: Yoshida
authors.affiliation: 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.
authors.forename: Ha Young
authors.initials: HY
authors.lastname: Cho
authors.affiliation: Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: J Patrick
authors.initials: JP
authors.lastname: Murphy
authors.affiliation: Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Diasynou
authors.initials: D
authors.lastname: Fioravante
authors.affiliation: Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Wade G
authors.initials: WG
authors.lastname: Regehr
authors.affiliation: Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Steven P
authors.initials: SP
authors.lastname: Gygi
authors.affiliation: Cutaneous Biology Research Center, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA.
authors.forename: Katia
authors.initials: K
authors.lastname: Georgopoulos
authors.affiliation: 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.
authors.forename: Azad
authors.initials: A
authors.lastname: Bonni
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001923:Brain Chemistry / Q000235:genetics*; D002478:Cells, Cultured; D042002:Chromatin Assembly and Disassembly / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics; D006801:Humans; D056245:Mi-2 Nucleosome Remodeling and Deacetylase Complex / Q000235:genetics*; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D011401:Promoter Regions, Genetic / Q000235:genetics*; D011689:Purkinje Cells / Q000502:physiology / Q000648:ultrastructure; D051381:Rats; D020318:Rats, Long-Evans; D017207:Rats, Sprague-Dawley; D056505:Retinoblastoma-Binding Protein 4 / Q000235:genetics; D013569:Synapses / Q000235:genetics* / Q000648:ultrastructure
chemical_list: D004268:DNA-Binding Proteins; C492012:Mbd3 protein, rat; D056505:Retinoblastoma-Binding Protein 4; D056245:Mi-2 Nucleosome Remodeling and Deacetylase Complex