Mammalian ISWI and SWI/SNF selectively mediate binding of distinct transcription factors,Nature

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Mammalian ISWI and SWI/SNF selectively mediate binding of distinct transcription factors
Nature ( IF 50.5 ) Pub Date : 2019-04-17 , DOI: 10.1038/s41586-019-1115-5
Darko Barisic _{1,

2,

3} , Michael B Stadler _{1,

4} , Mario Iurlaro ₁ , Dirk Schübeler _{1,

2}

Affiliation

Chromatin remodelling complexes evict, slide, insert or replace nucleosomes, which represent an intrinsic barrier for access to DNA. These remodellers function in most aspects of genome utilization including transcription-factor binding, DNA replication and repair1,2. Although they are frequently mutated in cancer3, it remains largely unclear how the four mammalian remodeller families (SWI/SNF, ISWI, CHD and INO80) orchestrate the global organization of nucleosomes. Here we generated viable embryonic stem cells that lack SNF2H, the ATPase of ISWI complexes, enabling study of SNF2H cellular function, and contrast it to BRG1, the ATPase of SWI/SNF. Loss of SNF2H decreases nucleosomal phasing and increases linker lengths, providing in vivo evidence for an ISWI function in ruling nucleosomal spacing in mammals. Systematic analysis of transcription-factor binding reveals that these remodelling activities have specific effects on binding of different transcription factors. One group critically depends on BRG1 and contains the transcriptional repressor REST, whereas a non-overlapping set of transcription factors, including the insulator protein CTCF, relies on SNF2H. This selectivity readily explains why chromosomal folding and insulation of topologically associated domains requires SNF2H, but not BRG1. Collectively, this study shows that mammalian ISWI is critical for nucleosomal periodicity and nuclear organization and that transcription factors rely on specific remodelling pathways for correct genomic binding.Genetic deletion of mammalian chromatin remodelling complexes reveals that ISWI and SWI/SNF are required for binding of specific transcription factors and that ISWI regulates nucleosome positioning and nuclear organization in stem cells.

中文翻译：

哺乳动物 ISWI 和 SWI/SNF 选择性介导不同转录因子的结合

染色质重塑复合物驱逐、滑动、插入或替换核小体，这是获取 DNA 的内在屏障。这些重塑剂在基因组利用的大多数方面发挥作用，包括转录因子结合、DNA 复制和修复1,2。尽管它们在癌症中经常发生突变，但在很大程度上仍不清楚四个哺乳动物重塑家族（SWI/SNF、ISWI、CHD 和 INO80）如何协调核小体的全球组织。在这里，我们生成了缺乏 SNF2H（ISWI 复合物的 ATP 酶）的存活胚胎干细胞，从而能够研究 SNF2H 细胞功能，并将其与 SWI/SNF 的 ATP 酶 BRG1 进行对比。SNF2H 的缺失减少了核小体的定相并增加了接头长度，为 ISWI 功能在哺乳动物中控制核小体间距提供了体内证据。对转录因子结合的系统分析表明，这些重塑活动对不同转录因子的结合具有特定的影响。一组严重依赖 BRG1 并包含转录抑制因子 REST，而一组不重叠的转录因子，包括绝缘蛋白 CTCF，依赖于 SNF2H。这种选择性很容易解释为什么拓扑相关域的染色体折叠和绝缘需要 SNF2H，而不是 BRG1。总的来说，这项研究表明哺乳动物 ISWI 对核小体周期性和核组织至关重要，并且转录因子依赖于特定的重塑途径来进行正确的基因组结合。

更新日期：2019-04-17

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