Super-enhancer-guided mapping of regulatory networks controlling mouse trophoblast stem cells

Bum-Kyu Lee,Jiwoon Lee,Samuel Beck,Mijeong Kim,Wenwen Shen,Lucy Leblanc,Jonghwan Kim,Yu Jin Jang,Catherine Rhee

doi:10.1038/s41467-019-12720-6

Bum-Kyu Lee, Jiwoon Lee + Show 7 more

Open Access

https://doi.org/10.1038/s41467-019-12720-6

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Journal: Nature Communications	Publication Date: Oct 18, 2019
Citations: 49	License type: open-access

Affiliation: The University of Texas at Austin

Abstract

Trophectoderm (TE) lineage development is pivotal for proper implantation, placentation, and healthy pregnancy. However, only a few TE-specific transcription factors (TFs) have been systematically characterized, hindering our understanding of the process. To elucidate regulatory mechanisms underlying TE development, here we map super-enhancers (SEs) in trophoblast stem cells (TSCs) as a model. We find both prominent TE-specific master TFs (Cdx2, Gata3, and Tead4), and >150 TFs that had not been previously implicated in TE lineage, that are SE-associated. Mapping targets of 27 SE-predicted TFs reveals a highly intertwined transcriptional regulatory circuitry. Intriguingly, SE-predicted TFs show 4 distinct expression patterns with dynamic alterations of their targets during TSC differentiation. Furthermore, depletion of a subset of TFs results in dysregulation of the markers for specialized cell types in placenta, suggesting a role during TE differentiation. Collectively, we characterize an expanded TE-specific regulatory network, providing a framework for understanding TE lineage development and placentation.

Highlights

Trophectoderm (TE) lineage development is pivotal for proper implantation, placentation, and healthy pregnancy
To identify enhancers utilized in trophoblast stem cells (TSCs), we first mapped the genomic occupancy of p300 using chromatin immunoprecipitation coupled with next-generation sequencing (ChIP-seq)
We found that syncytiotrophoblast layer II (SynT-II) marker genes (Gcm[1] and SynB) seem to show similar expression patterns that are somewhat opposite to syncytiotrophoblast layer I (SynT-I) marker (SynA) upon KD of TSC-specific transcription factors (TFs) such as Elf[5], Hopx, Id2, Pou3f1, and Zfpm[1] (Fig. 5b), which provide a possibility that these TFs might play dual function by suppressing trophoblast giant cells (TGCs)/SpT/ SynT-I differentiation while promoting SynT-II differentiation

Summary

Introduction

Trophectoderm (TE) lineage development is pivotal for proper implantation, placentation, and healthy pregnancy. To elucidate regulatory mechanisms underlying TE development, here we map super-enhancers (SEs) in trophoblast stem cells (TSCs) as a model We find both prominent TE-specific master TFs (Cdx[2], Gata[3], and Tead4), and >150 TFs that had not been previously implicated in TE lineage, that are SE-associated. In contrast to embryonic stem cells (ESCs), derived from the inner cell mass[4] and intensively researched due to their pluripotency, trophoblast stem cells (TSCs) established from an outgrowth of either polar TE or extraembryonic ectoderm[5] have not been studied nearly as much, despite the importance of the placenta This paucity of research has led to only a rudimentary understanding of the mechanisms underlying TE lineage specification, maintenance, and differentiation. The precise transcriptional regulatory mechanisms of TE/TSC-specific TFs remain elusive

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