Polycomb repressive complex 2 shields naïve human pluripotent cells from trophectoderm differentiation

Abstract

The first lineage choice in human embryo development separates trophectoderm from the inner cell mass. Naïve human embryonic stem cells are derived from the inner cell mass and offer possibilities to explore how lineage integrity is maintained. Here, we discover that polycomb repressive complex 2 (PRC2) maintains naïve pluripotency and restricts differentiation to trophectoderm and mesoderm lineages. Through quantitative epigenome profiling, we found that a broad gain of histone H3 lysine 27 trimethylation (H3K27me3) is a distinct feature of naïve pluripotency. We define shared and naïve-specific bivalent promoters featuring PRC2-mediated H3K27me3 concomitant with H3K4me3. Naïve bivalency maintains key trophectoderm and mesoderm transcription factors in a transcriptionally poised state. Inhibition of PRC2 forces naïve human embryonic stem cells into an ‘activated’ state, characterized by co-expression of pluripotency and lineage-specific transcription factors, followed by differentiation into either trophectoderm or mesoderm lineages. In summary, PRC2-mediated repression provides a highly adaptive mechanism to restrict lineage potential during early human development.

Integrated multi-omics reveal polycomb repressive complex 2 restricts human trophoblast induction

“…Our experiments showed that PRC2 inhibition was indeed not sufficient to increase the efficiency of trophoblast-fate induction in primed hPSCs to levels that are comparable to naive hPSCs. Many of our conclusions are in line with another study published in this issue 73 . One of the few differences between the two studies relates to whether PRC2 inhibition causes naive hPSCs to differentiate in self-renewing conditions.…”

“…One of the few differences between the two studies relates to whether PRC2 inhibition causes naive hPSCs to differentiate in self-renewing conditions. We found there is no miscellaneous differentiation of naive hPSCs following PRC2 inhibition with UNC1999 in PXGL medium, whereas Kumar et al 73 report significant levels of differentiation of naive hPSCs following PRC2 inhibition with EPZ-6438 in t2iLGö media. We tested whether this difference could be due to the different inhibitors used.…”

Roles of Polycomb Complexes in the Reconstruction of 3D Genome Architecture during Preimplantation Embryonic Development

“…However, in naïve human ESCs (hESCs), PcG complexes keep the promoters of genes coding TFs involved in the differentiation towards cell fates, such as the trophectoderm and mesoderm, in a bivalent state to shield them from premature transcriptional activation. Inhibition of PRC2 using an EZH2 inhibitor forces naïve hESCs to differentiate into either trophectoderm or mesoderm lineages [ 96 ]. The above findings indicate that during the process of pluripotency maintenance in ESCs, further exploration into how PcG complexes are recruited to these sites and which TFs they can interact with, as well as the specific mechanisms of how PcG complexes are erased in the process of differentiation, is needed.…”

The Role of Polycomb Proteins in Cell Lineage Commitment and Embryonic Development

“…Although the studies were conducted using various loss-of-function methods, the picture emerged that embryos could not survive past gastrulation, without the PRC2 core proteins [ 17 , 55 , 56 ]. Recent studies identified an important role for PRC2 in restricting trophoblast induction in human naïve pluripotent stem cells in vitro [ 57 , 58 ], suggesting a role in the earliest mammalian lineage decision after fertilization. In PRC1, the loss of RING1B protein results in developmental arrest at E6.5, during gastrulation, but RING1A mutants were able to survive and reach birth, although displaying defects in transformation of the axial skeleton and altered levels of Hox gene expression [ 59 , 60 ].…”