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

• Published in: Nature communications Vol. 5; no. 1; p. 4181
• Main Authors: Alvarez-Saavedra, Matías, De Repentigny, Yves, Lagali, Pamela S., Raghu Ram, Edupuganti V. S., Yan, Keqin, Hashem, Emile, Ivanochko, Danton, Huh, Michael S., Yang, Doo, Mears, Alan J., Todd, Matthew A. M., Corcoran, Chelsea P., Bassett, Erin A., Tokarew, Nicholas J. A., Kokavec, Juraj, Majumder, Romit, Ioshikhes, Ilya, Wallace, Valerie A., Kothary, Rashmi, Meshorer, Eran, Stopka, Tomas, Skoultchi, Arthur I., Picketts, David J.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 20-06-2014; Nature Publishing Group; Nature Pub. Group
• Subjects: 13; 13/51; 14; 14/19; 38; 38/15; 38/61; 631/136/1660; 631/337/176; 631/378/2632/1368; 64; 64/110; 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; Humanities and Social Sciences; 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; multidisciplinary; Neural Stem Cells - metabolism; Neural Stem Cells - physiology; Purkinje Cells - metabolism; Real-Time Polymerase Chain Reaction; Reverse Transcriptase Polymerase Chain Reaction; Rotarod Performance Test; Science; Science (multidisciplinary); Tolonium Chloride
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/ncomms5181

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.
The chromatin remodelling proteins Snf2h and Snf2l regulate nucleosome spacing. Here, the authors show that
Snf2h
ablation impairs chromatin organization of neuronal lineages during mouse embryonic and post-natal cerebellar development.