Panamarova Maryna, Cox Andy, Wicher Krzysztof B, Butler Richard, Bulgakova Natalia, Jeon Shin, Rosen Barry, Seong Rho H, Skarnes William, Crabtree Gerald, Zernicka-Goetz Magdalena
Wellcome Trust Cancer Research UK Gurdon Institute, Tennis Court Road, Cambridge CB2 1QN, UK Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge CB2 3DY, UK.
Wellcome Trust Cancer Research UK Gurdon Institute, Tennis Court Road, Cambridge CB2 1QN, UK.
Development. 2016 Apr 15;143(8):1271-83. doi: 10.1242/dev.131961. Epub 2016 Mar 7.
Dynamic control of gene expression is essential for the development of a totipotent zygote into an embryo with defined cell lineages. The accessibility of genes responsible for cell specification to transcriptional machinery is dependent on chromatin remodelling complexes such as the SWI\SNF (BAF) complex. However, the role of the BAF complex in early mouse development has remained unclear. Here, we demonstrate that BAF155, a major BAF complex subunit, regulates the assembly of the BAF complex in vivo and regulates lineage specification of the mouse blastocyst. We find that associations of BAF155 with other BAF complex subunits become enriched in extra-embryonic lineages just prior to implantation. This enrichment is attributed to decreased mobility of BAF155 in extra-embryonic compared with embryonic lineages. Downregulation of BAF155 leads to increased expression of the pluripotency marker Nanog and its ectopic expression in extra-embryonic lineages, whereas upregulation of BAF155 leads to the upregulation of differentiation markers. Finally, we show that the arginine methyltransferase CARM1 methylates BAF155, which differentially influences assembly of the BAF complex between the lineages and the expression of pluripotency markers. Together, our results indicate a novel role of BAF-dependent chromatin remodelling in mouse development via regulation of lineage specification.
基因表达的动态控制对于全能受精卵发育成具有特定细胞谱系的胚胎至关重要。负责细胞特化的基因对转录机制的可及性取决于染色质重塑复合物，如SWI\SNF（BAF）复合物。然而，BAF复合物在小鼠早期发育中的作用仍不清楚。在这里，我们证明BAF复合物的主要亚基BAF155在体内调节BAF复合物的组装，并调节小鼠囊胚的谱系特化。我们发现，就在着床前，BAF155与其他BAF复合物亚基的结合在胚外谱系中变得富集。这种富集归因于与胚胎谱系相比，BAF155在胚外谱系中的移动性降低。BAF155的下调导致多能性标志物Nanog的表达增加及其在胚外谱系中的异位表达，而BAF155的上调导致分化标志物的上调。最后，我们表明精氨酸甲基转移酶CARM1使BAF155甲基化，这对谱系间BAF复合物的组装和多能性标志物的表达有不同影响。总之，我们的结果表明BAF依赖的染色质重塑通过调节谱系特化在小鼠发育中具有新作用。
