Smarcb1 maintains the cellular identity and the chromatin landscapes of mouse embryonic stem cells
Smarcb1 maintains the cellular identity and the chromatin landscapes of mouse embryonic stem cells
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DOI：
10.1016/j.bbrc.2019.09.054
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发表时间：
2019-11-19
影响因子：
3.1
通讯作者：
Yamada, Yasuhiro
中科院分区：
文献类型：
--
作者：
Sakakura, Megumi;Ohta, Sho;Yamada, Yasuhiro
ES细胞（ESC）身份通过转录因子和染色质结构的协调调节而稳定维持。 SMARCB1，也称为 INI1、SNF5、BAF47，是 SWI/SNF (BAF) 复合物的亚基之一，通过控制染色质动力学在调节基因表达方面发挥着至关重要的作用。小鼠中 Smarcb1 的基因消除会导致胚胎在着床阶段死亡，表明 Smarcb1 对于早期发育阶段很重要。然而，SMARCB1 在维持 ESC 特性中的作用仍然未知。在这里，我们建立了缺乏 Smarcb1 的小鼠 ESC，并研究了 Smarcb1 敲除对 ESC 分化倾向的影响。我们发现 Smarcb1 缺陷的 ESC 中滋养外胚层相关基因（包括 Cdx2）的表达增加。一致地，它们表现出向畸胎瘤中的滋养外胚层谱系细胞的扩展分化倾向。然而，尽管Smarcb1缺陷细胞很少被整合到囊胚的滋养外胚层细胞层中，但它们无法在体内形成成熟的胎盘组织。此外，Smarcbl缺陷细胞在E14.5嵌合胚胎的神经组织中表现出过早分化。值得注意的是，我们发现参与基因组 DNA 结构维持的 CTCF 结合基序在 Smarcb1 缺陷细胞中的染色质区域显着富集，其可及性增强，而多能性因子的结合基序在这些细胞中具有更封闭结构的区域中过度呈现。总的来说，我们认为 SMARCB1 介导的染色质景观重塑对于 ESC 的维持和分化很重要。 (C) 2019 Elsevier Inc. 保留所有权利。
ES cell (ESC) identity is stably maintained through the coordinated regulation of transcription factors and chromatin structure. SMARCB1, also known as INI1, SNF5, BAF47, is one of the subunits of SWI/SNF (BAF) complexes that play a crucial role in regulating gene expression by controlling chromatin dynamics. Genetic ablation of Smarcb1 in mice leads to embryonic lethality at the pen-implantation stage, indicating that Smarcb1 is important for the early developmental stages. However, the role of SMARCB1 in the maintenance of the ESC identity remains unknown. Here we established mouse ESCs lacking Smarcb1 and investigated the effect of Smarcb1 ablation on the differentiation propensity of ESCs. We found an increased expression of trophectoderm-related genes including Cdx2 in Smarcb1-deficient ESCs. Consistently, they exhibited an extended differentiation propensity into the trophectoderm lineage cells in teratomas. However, although Smarcb1-deficient cells were infrequently incorporated into the trophectoderm cell layer of blastocysts, they failed to contribute to mature placental tissues in vivo. Furthermore, Smarcbl-deficient cells exhibited a premature differentiation in the neural tissue of E14.5 chimeric embryos. Notably, we found that binding motifs for CTCF, which is involved in the maintenance of genomic DNA architecture was significantly enriched in chromatin regions whose accessibility was augmented in Smarcb1-deficient cells, while those for pluripotency factors were overrepresented in regions which have more closed structure in those cells. Collectively, we propose that SMARCB1-mediated remodeling of chromatin landscapes is important for the maintenance and differentiation of ESCs. (C) 2019 Elsevier Inc. All rights reserved.