Abstract
Trophoblast stem cells (TSCs) give rise to specialized cell types within the placenta. However, the regulatory mechanisms that guide trophoblast cell fate decisions during placenta development remain ill defined. Here we exploited ATAC-seq and transcriptional profiling strategies to describe dynamic changes in gene expression and chromatin accessibility during TSC differentiation. We detect significantly increased chromatin accessibility at key genes upregulated as TSCs exit from the stem cell state. However, downregulated gene expression is not simply due to the loss of chromatin accessibility in proximal regions. Additionally, transcriptional targets recognized by the zinc finger transcriptional repressor Prdm1/Blimp1, an essential regulator of placenta development, were identified in ChIP-seq experiments. Comparisons with previously reported ChIP-seq datasets for primordial germ cell-like cells and E18.5 small intestine, combined with functional annotation analysis revealed that Blimp1 has broadly shared as well as cell type-specific functional activities unique to the trophoblast lineage. Importantly, Blimp1 not only silences TSC gene expression but also prevents aberrant activation of divergent developmental programmes. Overall the present study provides new insights into the chromatin landscape and Blimp1-dependent regulatory networks governing trophoblast gene expression.
Highlights
The placenta, a specialized organ comprised of both maternal and foetal tissues is essential to support mammalian embryonic development[1]
We found that ~45% of Trophoblast stem cells (TSCs) ATAC-seq peaks were shared with embryonic stem cells (ESCs), as opposed to ~20% shared with the 8-cell dataset (Fig. 1A, Supplementary Table S1, Supplementary Fig. S2)
To determine whether TSC ATAC-seq peaks overlapping with 8-cell and ESC data may represent distinct classes of cis-regulatory elements (CREs) we used published TSC histone modification data[9]. This revealed that a high proportion of TSC ATAC-seq peaks, including those shared with 8-cell embryos are putative enhancers (H3K4me1/H3K27ac positive), while those shared with ESCs are more likely to be promoters (H3K4me3/H3K27ac positive; Fig. 1F)
Summary
The placenta, a specialized organ comprised of both maternal and foetal tissues is essential to support mammalian embryonic development[1]. The ExE contains the progenitors of specialized syncytiotrophoblasts that mediate maternal-foetal exchange in the placental labyrinth region, whereas the EPC gives rise to the outer spongiotrophoblast (SpT) layer - the source of diverse trophoblast giant cells (TGCs) including the spiral artery-associated trophoblast giant cells (SpA-TGCs) that invade the maternal uterine tissue and replace arterial linings to promote increased blood flow to the foetus[2, 3]. To learn more about transcriptional and epigenetic mechanisms controlling maturation of various trophoblast cell types, here we exploited ATAC-seq technology[21] to describe global chromatin accessibility changes associated with loss of the stem cell state and the emergence of the Blimp1+ trophoblast cell lineage. Combined with functional annotation analysis and comparisons with published microarray datasets, collectively the present genome-wide analyses reveal key features of the chromatin landscape controlling trophoblast gene expression profiles and advance our understanding of the signalling pathways that regulate development of the trophoblast cell lineage
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