Abstract
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.
Highlights
Differentiation involves a cascade of cell fate decisions that progressively limit the potential of a cell to contribute to other lineages
We analysed the distribution of BAF complex subunits: a catalytic subunit BRG1; a scaffolding subunit BAF155 and its homologue BAF170 (SMARCC2); and subunit BAF57, which contributes to DNA binding (Link et al, 2005; Chi et al, 2002; Phelan et al, 1999; Sohn et al, 2007)
We found that BRG1, BAF155 and BAF57 are expressed in all cell lineages, whereas BAF170 is not expressed (Fig. 1A, Fig. S1A)
Summary
Differentiation involves a cascade of cell fate decisions that progressively limit the potential of a cell to contribute to other lineages. Two cell fate decisions take place in the pre-implantation mouse embryo The first of these causes the separation of the inner cell mass (ICM) from trophectoderm (TE), the first extra-embryonic lineage; the second leads to the formation of two distinct cell populations from the ICM: pluripotent epiblast (EPI) and primitive endoderm (PE), which forms the second extra-embryonic lineage. Differential behaviour of the protein complexes and chromatinmodifying enzymes that alter the structure of chromatin is required in concert with transcription factors to regulate appropriate gene expression for these processes (Paul and Knott, 2014)
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