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

Matías Alvarez-Saavedra, Yves De Repentigny, Pamela S. Lagali, Edupuganti V. S. Raghu Ram, Keqin Yan, Emile Hashem, Danton Ivanochko, Michael S. Huh, Doo Yang, Alan J. Mears, Matthew A. M. Todd, Chelsea P. Corcoran, Erin A. Bassett, Nicholas J. A. Tokarew, Juraj Kokavec, Romit Majumder, Ilya Ioshikhes, Valerie A. Wallace, Rashmi Kothary, Eran Meshorer, Tomas Stopka, Arthur I. Skoultchi and David J. Picketts ()
Additional contact information
Matías Alvarez-Saavedra: Regenerative Medicine Program, Ottawa Hospital Research Institute
Yves De Repentigny: Regenerative Medicine Program, Ottawa Hospital Research Institute
Pamela S. Lagali: Regenerative Medicine Program, Ottawa Hospital Research Institute
Edupuganti V. S. Raghu Ram: The Alexander Silberman Institute of Life Sciences, The Hebrew University of Jerusalem
Keqin Yan: Regenerative Medicine Program, Ottawa Hospital Research Institute
Emile Hashem: Regenerative Medicine Program, Ottawa Hospital Research Institute
Danton Ivanochko: Regenerative Medicine Program, Ottawa Hospital Research Institute
Michael S. Huh: Regenerative Medicine Program, Ottawa Hospital Research Institute
Doo Yang: Microbiology and Immunology, University of Ottawa
Alan J. Mears: Vision Program, Ottawa Hospital Research Institute
Matthew A. M. Todd: Regenerative Medicine Program, Ottawa Hospital Research Institute
Chelsea P. Corcoran: Regenerative Medicine Program, Ottawa Hospital Research Institute
Erin A. Bassett: Microbiology and Immunology, University of Ottawa
Nicholas J. A. Tokarew: Microbiology and Immunology, University of Ottawa
Juraj Kokavec: Institute of Pathologic Physiology, First Faculty of Medicine, Charles University in Prague
Romit Majumder: Albert Einstein College of Medicine
Ilya Ioshikhes: Microbiology and Immunology, University of Ottawa
Valerie A. Wallace: Microbiology and Immunology, University of Ottawa
Rashmi Kothary: Regenerative Medicine Program, Ottawa Hospital Research Institute
Eran Meshorer: The Alexander Silberman Institute of Life Sciences, The Hebrew University of Jerusalem
Tomas Stopka: Institute of Pathologic Physiology, First Faculty of Medicine, Charles University in Prague
Arthur I. Skoultchi: Albert Einstein College of Medicine
David J. Picketts: Regenerative Medicine Program, Ottawa Hospital Research Institute

Nature Communications, 2014, vol. 5, issue 1, 1-18

Abstract: 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.

Date: 2014
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DOI: 10.1038/ncomms5181

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