Super-Enhancers and CTCF in Early Embryonic Cell Fate Decisions

Abstract

Cell fate decisions are the backbone of many developmental and disease processes. In early mammalian development, precise gene expression changes underly the rapid division of a single cell that leads to the embryo and are critically dependent on autonomous cell changes in gene expression. To understand how these lineage specifications events are mediated, scientists have had to look past protein coding genes to the cis regulatory elements (CREs), including enhancers and insulators, that modulate gene expression. One class of enhancers, termed super-enhancers, is highly active and cell-type specific, implying their critical role in modulating cell-type specific gene expression. Deletion or mutations within these CREs adversely affect gene expression and development and can cause disease. In this mini-review we discuss recent studies describing the potential roles of two CREs, enhancers and binding sites for CTCF, in early mammalian development.

Keywords: CTCF; embryonic stem cell; enhancer; nanog; pluripotency.

FIGURE 1

Nanog Super-enhancers. (A) Schematic of the Nanog extended locus with the three SEs. Schematic of a theoretical loop containing all three SEs and Nanog depicting. (B) The changes in Nanog expression upon deletion (Blinka et al., 2016; Agrawal et al., 2021). (C) The interaction between the −5SE and Nanog and how it alters RNAPII dynamics (Agrawal et al., 2021). (D) The interaction between the −45SE and Nanog and its potential mechanisms. (E) The interaction between the +60SE and Nanog and the possible backup role it has in regulating the gene.

FIGURE 2

TADs and CTCF. (A) Schematic of chromatin organization. The triangles depict a schematic of a Hi-C contact map. White arcs show the intra-TAD interactions that are insulated by CTCF. (B) Schematic of what a Hi-C contact map may look like upon CTCF depletion. White arcs show the gained interactions across previous TAD boundaries.