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 et al.
Nature Communications 5, Article number: 4181 doi:10.1038/ncomms5181
Received 12 February 2014 Accepted 15 May 2014 Published 20 June 2014
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.
Subject terms: Biological sciences Developmental biology Molecular biology Neuroscience
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