Chromatin remodeling proteins utilize the energy from ATP hydrolysis to mobilize nucleosomes often creating accessibility for transcription factors within gene regulatory elements. Aberrant chromatin remodeling has diverse effects on neuroprogenitor homeostasis altering progenitor competence, proliferation, survival, or cell fate. Previous work has shown that inactivation of the ISWI genes, Smarca5 (encoding Snf2h) and Smarca1 (encoding Snf2l) have dramatic effects on brain development. Smarca5 conditional knockout mice have reduced progenitor expansion and severe forebrain hypoplasia, with a similar effect on the postnatal growth of the cerebellum. In contrast, Smarca1 mutants exhibited enlarged forebrains with delayed progenitor differentiation and increased neuronal output. Here, we utilized cerebellar granule neuron precursor (GNP) cultures from Smarca1 mutant mice (Ex6DEL) to explore the requirement for Snf2l on progenitor homeostasis. The Ex6DEL GNPs showed delayed differentiation upon plating that was not attributed to changes in the Sonic Hedgehog pathway but was associated with overexpression of numerous positive effectors of proliferation, including targets of Wnt activation. Transcriptome analysis identified increased expression of Fosb and Fosl2 while ATACseq experiments identified a large increase in chromatin accessibility at promoters many enriched for Fos/Jun binding sites. Nonetheless, the elevated proliferation index was transient and the Ex6DEL cultures initiated differentiation with a high concordance in gene expression changes to the wild type cultures. Genes specific to Ex6DEL differentiation were associated with an increased activation of the ERK signaling pathway. Taken together, this data provides the first indication of how Smarca1 mutations alter progenitor cell homeostasis and contribute to changes in brain size.

中文翻译：

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受损的 SNF2L 染色质重塑延长了富含 Fos/Jun 结合位点的启动子的可及性，并延迟了颗粒神经元分化

染色质重塑蛋白利用来自 ATP 水解的能量来动员核小体，通常为基因调控元件内的转录因子创造可及性。异常染色质重塑对神经祖细胞稳态具有多种影响，可改变祖细胞能力、增殖、存活或细胞命运。以前的工作表明，ISWI 基因 Smarca5（编码 Snf2h）和 Smarca1（编码 Snf2l）的失活对大脑发育具有显着影响。Smarca5 条件性敲除小鼠的祖细胞扩增减少和严重的前脑发育不全，对小脑的出生后生长也有类似的影响。相比之下，Smarca1 突变体表现出前脑增大，祖细胞分化延迟和神经元输出增加。这里，我们利用来自 Smarca1 突变小鼠（Ex6DEL）的小脑颗粒神经元前体（GNP）培养物来探索 Snf2l 对祖细胞稳态的需求。Ex6DEL GNP 在铺板时表现出延迟分化，这并非归因于 Sonic Hedgehog 通路的变化，而是与许多阳性增殖效应子的过度表达有关，包括 Wnt 激活的目标。转录组分析确定了 Fosb 和 Fosl2 的表达增加，而 ATACseq 实验确定了许多富含 Fos/Jun 结合位点的启动子染色质可及性的大量增加。尽管如此，升高的增殖指数是暂时的，Ex6DEL 培养物开始分化，基因表达变化与野生型培养物高度一致。Ex6DEL 分化特异性基因与 ERK 信号通路的激活增加有关。总之，这些数据提供了 Smarca1 突变如何改变祖细胞稳态并导致大脑大小变化的第一个迹象。