title: Snf2h-mediated chromatin organization and histone H1 dynamics govern cerebellar morphogenesis and neural maturation.
abstract: Chromatin compaction mediates progenitor to post-mitotic cell transitions and modulates gene expression programs, yet the mechanisms are poorly defined. Snf2h and Snf2l are ATP-dependent chromatin remodelling proteins that assemble, reposition and space nucleosomes, and are robustly expressed in the brain. Here we show that mice conditionally inactivated for Snf2h in neural progenitors have reduced levels of histone H1 and H2A variants that compromise chromatin fluidity and transcriptional programs within the developing cerebellum. Disorganized chromatin limits Purkinje and granule neuron progenitor expansion, resulting in abnormal post-natal foliation, while deregulated transcriptional programs contribute to altered neural maturation, motor dysfunction and death. However, mice survive to young adulthood, in part from Snf2l compensation that restores Engrailed-1 expression. Similarly, Purkinje-specific Snf2h ablation affects chromatin ultrastructure and dendritic arborization, but alters cognitive skills rather than motor control. Our studies reveal that Snf2h controls chromatin organization and histone H1 dynamics for the establishment of gene expression programs underlying cerebellar morphogenesis and neural maturation.
authors.affiliation: 1] Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada K1H 8L6 [2] Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, Ontario, Canada K1H 8M5.
authors.forename: Matías
authors.initials: M
authors.lastname: Alvarez-Saavedra
authors.affiliation: Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada K1H 8L6.
authors.forename: Yves
authors.initials: Y
authors.lastname: De Repentigny
authors.affiliation: Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada K1H 8L6.
authors.forename: Pamela S
authors.initials: PS
authors.lastname: Lagali
authors.affiliation: Department of Genetics, The Alexander Silberman Institute of Life Sciences, The Hebrew University of Jerusalem, Jerusalem 91904, Israel.
authors.forename: Edupuganti V S
authors.initials: EV
authors.lastname: Raghu Ram
authors.affiliation: Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada K1H 8L6.
authors.forename: Keqin
authors.initials: K
authors.lastname: Yan
authors.affiliation: 1] Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada K1H 8L6 [2] Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, Ontario, Canada K1H 8M5.
authors.forename: Emile
authors.initials: E
authors.lastname: Hashem
authors.affiliation: 1] Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada K1H 8L6 [2] Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, Ontario, Canada K1H 8M5.
authors.forename: Danton
authors.initials: D
authors.lastname: Ivanochko
authors.affiliation: Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada K1H 8L6.
authors.forename: Michael S
authors.initials: MS
authors.lastname: Huh
authors.affiliation: 1] Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, Ontario, Canada K1H 8M5 [2] Institute of Systems Biology, University of Ottawa, Ottawa, Ontario, Canada K1H 8M5.
authors.forename: Doo
authors.initials: D
authors.lastname: Yang
authors.affiliation: Vision Program, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada K1H 8L6.
authors.forename: Alan J
authors.initials: AJ
authors.lastname: Mears
authors.affiliation: 1] Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada K1H 8L6 [2] Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, Ontario, Canada K1H 8M5.
authors.forename: Matthew A M
authors.initials: MA
authors.lastname: Todd
authors.affiliation: Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada K1H 8L6.
authors.forename: Chelsea P
authors.initials: CP
authors.lastname: Corcoran
authors.affiliation: Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, Ontario, Canada K1H 8M5.
authors.forename: Erin A
authors.initials: EA
authors.lastname: Bassett
authors.affiliation: Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, Ontario, Canada K1H 8M5.
authors.forename: Nicholas J A
authors.initials: NJ
authors.lastname: Tokarew
authors.affiliation: Institute of Pathologic Physiology, First Faculty of Medicine, Charles University in Prague, Prague 12853, Czech Republic.
authors.forename: Juraj
authors.initials: J
authors.lastname: Kokavec
authors.affiliation: Department of Cell Biology, Albert Einstein College of Medicine, Bronx, New York 10461, USA.
authors.forename: Romit
authors.initials: R
authors.lastname: Majumder
authors.affiliation: 1] Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, Ontario, Canada K1H 8M5 [2] Institute of Systems Biology, University of Ottawa, Ottawa, Ontario, Canada K1H 8M5.
authors.forename: Ilya
authors.initials: I
authors.lastname: Ioshikhes
authors.affiliation: 1] Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, Ontario, Canada K1H 8M5 [2] Vision Program, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada K1H 8L6.
authors.forename: Valerie A
authors.initials: VA
authors.lastname: Wallace
authors.affiliation: 1] Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada K1H 8L6 [2] Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, Ontario, Canada K1H 8M5.
authors.forename: Rashmi
authors.initials: R
authors.lastname: Kothary
authors.affiliation: Department of Genetics, The Alexander Silberman Institute of Life Sciences, The Hebrew University of Jerusalem, Jerusalem 91904, Israel.
authors.forename: Eran
authors.initials: E
authors.lastname: Meshorer
authors.affiliation: Institute of Pathologic Physiology, First Faculty of Medicine, Charles University in Prague, Prague 12853, Czech Republic.
authors.forename: Tomas
authors.initials: T
authors.lastname: Stopka
authors.affiliation: Department of Cell Biology, Albert Einstein College of Medicine, Bronx, New York 10461, USA.
authors.forename: Arthur I
authors.initials: AI
authors.lastname: Skoultchi
authors.affiliation: 1] Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada K1H 8L6 [2] Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, Ontario, Canada K1H 8M5 [3] Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, Ontario, Canada K1H 8M5.
authors.forename: David J
authors.initials: DJ
authors.lastname: Picketts
mesh_terms: D000251:Adenosine Triphosphatases / Q000378:metabolism*; D000704:Analysis of Variance; D000818:Animals; D015153:Blotting, Western; D001973:Bromodeoxyuridine; D002531:Cerebellum / Q000196:embryology*; D042002:Chromatin Assembly and Disassembly / Q000502:physiology*; D047369:Chromatin Immunoprecipitation; D002868:Chromosomal Proteins, Non-Histone / Q000378:metabolism*; D005260:Female; D005453:Fluorescence; D005697:Galactosides; D018507:Gene Expression Regulation, Developmental / Q000235:genetics / Q000502:physiology*; D006657:Histones / Q000378:metabolism*; D018398:Homeodomain Proteins / Q000378:metabolism; D007091:Image Processing, Computer-Assisted; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D020287:In Situ Nick-End Labeling; D007211:Indoles; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D046228:Microarray Analysis; D046529:Microscopy, Electron, Transmission; D009024:Morphogenesis / Q000235:genetics / Q000502:physiology*; D058953:Neural Stem Cells / Q000378:metabolism / Q000502:physiology*; D011689:Purkinje Cells / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D045442:Rotarod Performance Test; D014048:Tolonium Chloride
chemical_list: D002868:Chromosomal Proteins, Non-Histone; C080330:En1 protein, mouse; D005697:Galactosides; D006657:Histones; D018398:Homeodomain Proteins; D007211:Indoles; D014048:Tolonium Chloride; D000251:Adenosine Triphosphatases; C498725:Smarca5 protein, mouse; D001973:Bromodeoxyuridine; C044888:5-bromo-4-chloro-3-indolyl beta-galactoside