Snf2h-mediated chromatin organization and histone H1 dynamics govern cerebellar morphogenesis and neural maturation.
Snf2h-mediated chromatin organization and histone H1 dynamics govern cerebellar morphogenesis and neural maturation.
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SNF2H介导的染色质组织和组蛋白H1动力学控制小脑形态发生和神经成熟。
DOI：
10.1038/ncomms5181
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发表时间：
2014-06-20
影响因子：
16.6
通讯作者：
Picketts, David J.
中科院分区：
文献类型：
--
作者：
Alvarez-Saavedra, Matias;De Repentigny, Yves;Lagali, Pamela S.;Ram, Edupuganti V. S. Raghu;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.
染色质致密化介导祖细胞到有丝分裂后细胞的转变，并调节基因表达程序，但其机制尚不清楚。Snf 2 h和Snf 2l是ATP依赖性染色质重塑蛋白，其组装、重新定位和间隔核小体，并且在脑中稳健表达。在这里，我们表明，小鼠有条件失活的神经祖细胞中的Snf 2 h组蛋白H1和H2 A变体的水平降低，损害染色质流动性和转录程序在发育中的小脑。染色质紊乱限制了浦肯野和颗粒神经元祖细胞的扩增，导致出生后异常的叶状，而转录程序失调导致神经成熟改变、运动功能障碍和死亡。然而，小鼠存活到成年早期，部分原因是Snf 2l补偿恢复了Engrailed-1表达。类似地，浦肯野特异性Snf 2 h消融影响染色质超微结构和树突状分支，但改变认知技能而不是运动控制。我们的研究表明，Snf 2 h控制染色质组织和组蛋白H1动力学的基因表达程序的基础小脑形态发生和神经成熟的建立。 染色质重塑蛋白Snf 2 h和Snf 2l调节核小体间距。在这里，作者表明Snf 2 h消融损害小鼠胚胎和出生后小脑发育过程中神经元谱系的染色质组织。
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.
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