Snf2h-mediated chromatin organization and histone H1 dynamics govern cerebellar morphogenesis and neural maturation

Nat Commun. 2014 Jun 20;5:4181. doi: 10.1038/ncomms5181.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Triphosphatases / metabolism*
  • Analysis of Variance
  • Animals
  • Blotting, Western
  • Bromodeoxyuridine
  • Cerebellum / embryology*
  • Chromatin Assembly and Disassembly / physiology*
  • Chromatin Immunoprecipitation
  • Chromosomal Proteins, Non-Histone / metabolism*
  • Female
  • Fluorescence
  • Galactosides
  • Gene Expression Regulation, Developmental / genetics
  • Gene Expression Regulation, Developmental / physiology*
  • Histones / metabolism*
  • Homeodomain Proteins / metabolism
  • Image Processing, Computer-Assisted
  • Immunohistochemistry
  • In Situ Hybridization
  • In Situ Nick-End Labeling
  • Indoles
  • Male
  • Mice
  • Mice, Transgenic
  • Microarray Analysis
  • Microscopy, Electron, Transmission
  • Morphogenesis / genetics
  • Morphogenesis / physiology*
  • Neural Stem Cells / metabolism
  • Neural Stem Cells / physiology*
  • Purkinje Cells / metabolism
  • Real-Time Polymerase Chain Reaction
  • Reverse Transcriptase Polymerase Chain Reaction
  • Rotarod Performance Test
  • Tolonium Chloride

Substances

  • Chromosomal Proteins, Non-Histone
  • En1 protein, mouse
  • Galactosides
  • Histones
  • Homeodomain Proteins
  • Indoles
  • Tolonium Chloride
  • Adenosine Triphosphatases
  • Smarca5 protein, mouse
  • Bromodeoxyuridine
  • 5-bromo-4-chloro-3-indolyl beta-galactoside

Associated data

  • GEO/GSE42371