Smarcb1 maintains the cellular identity and the chromatin landscapes of mouse embryonic stem cells

• Published in: Biochemical and biophysical research communications Vol. 519; no. 4; pp. 705 - 713
• Main Authors: Sakakura, Megumi, Ohta, Sho, Yagi, Masaki, Tanaka, Akito, Norihide, Jo, Woltjen, Knut, Yamamoto, Takuya, Yamada, Yasuhiro
• Format: Journal Article
• Language: English
• Published: Elsevier Inc 19-11-2019
• Subjects: Chromatin accessibility; Embryonic stem cell; Pluripotency; Smarcb1; Trophectoderm; Trophectoderm; Embryonic stem cell; Chromatin accessibility; Smarcb1; Pluripotency
• ISSN: 0006-291X; 1090-2104
• DOI: 10.1016/j.bbrc.2019.09.054

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 peri-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, Smarcb1-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.
•Smarcb1-deficient ES cells exhibit an increased expression of trophectoderm-related genes including Cdx2.•Smarcb1-deficient ES cells retain pluripotency but exhibit an impaired differentiation in vivo.•SMARCB1-mediated remodeling of chromatin landscapes may be important for the maintenance and differentiation of ESCs.