Keep the fate: how chromatin regulators safeguard embryonic stem cell identity

Abstract

Segregation of cells that form the embryo from those that produce the surrounding extra-embryonic tissues is critical for early mammalian development, but the regulatory layers governing these first cell fate decisions remain poorly understood. Recent work in The EMBO Journal identifies two chromatin regulators, Hdac3 and Dax1, that synergistically restrict the developmental potential of mouse embryonic stem cells and act as a lineage barrier to primitive endoderm formation.

Figure 1. Histone deacetylase Hdac3 and nuclear receptor Dax1 as lineage barriers to primitive endoderm formation in mESCs

(A) The first three lineages in the mouse preimplantation embryo at the blastocyst stage. (B) The transition from mESCs to PE‐like cells can be induced by deleting a pluripotency‐associated gene, Nanog, or by overexpression of the endoderm‐associated gene Gata6. In addition, HDAC3 and DAX1 act as additional barriers for this transition, safeguarding the EPI identity of mESCs. (C) The genetically engineered reporter mESC lines used by Olivieri et al (2021). The EPI‐specific gene Nanog is tagged with a green fluorescent protein (GFP), and the PE‐specific gene Gata6 is coupled with a red fluorescent protein (mCherry). Cells in the EPI‐like state activate the GFP reporter only, while cells in the PE‐like state activate only mCherry. (D) The molecular mechanism by which HDAC3 safeguards the identity of mESCs. By binding to Gata6 enhancer region—enh^‐45, HDAC3 inhibits the activation of the Gata6 gene which is required to activate PE genes. Removal of HDAC3 allows Gata6 expression and its binding to cis‐regulatory elements of PE genes, thus enabling induction of PE‐like cell identity.