Super-Enhancers in Placental Development and Diseases

Abstract

The proliferation of trophoblast stem (TS) cells and their differentiation into multiple lineages are pivotal for placental development and functions. Various transcription factors (TFs), such as CDX2, EOMES, GATA3, TFAP2C, and TEAD4, along with their binding sites and cis-regulatory elements, have been studied for their roles in trophoblast cells. While previous studies have primarily focused on individual enhancer regions in trophoblast development and differentiation, recent attention has shifted towards investigating the role of super-enhancers (SEs) in different trophoblast cell lineages. SEs are clusters of regulatory elements enriched with transcriptional regulators, forming complex gene regulatory networks via differential binding patterns and the synchronized stimulation of multiple target genes. Although the exact role of SEs remains unclear, they are commonly found near master regulator genes for specific cell types and are implicated in the transcriptional regulation of tissue-specific stem cells and lineage determination. Additionally, super-enhancers play a crucial role in regulating cellular growth and differentiation in both normal development and disease pathologies. This review summarizes recent advances on SEs' role in placental development and the pathophysiology of placental diseases, emphasizing the potential for identifying SE-driven networks in the placenta to provide valuable insights for developing therapeutic strategies to address placental dysfunctions.

Keywords: placental development; placental diseases; super-enhancers; transcriptional regulators; trophoblast stem cells.

Figure 1

Graphic illustration of differences between typical enhancers and super-enhancers (SEs). (A) Structural differences between typical enhancers (a) and SEs (b). (B) Transcriptional loops/networks of typical enhancers (c) and SEs (d). E, enhancer regions; P, promoter of the gene; TSS, transcription start site; TF, transcription factor; MED, mediator subunit 1; RNAP II, RNA polymerase II; and Ac, acetylation.

Figure 2

Comparative anatomy of human and mouse placenta. (A) Schematic representation of the human placenta illustrating the maternal and fetal surfaces, which are attached by the maternal decidua and the associated vasculature. MA, maternal artery; MV, maternal vein; Myo, myometrium; Dec, decidua; CV, chorionic villus; Cho, Chorion; UA, umbilical artery; and UV, umbilical vein. (B) Schematic representation of the rodent placenta showing the labyrinth (LZ) and junctional zones (JZ) that are overlaid by the mesometrial triangle (MT). The labyrinth zone is rich in maternal and fetal blood vessels (BV) and syncytiotrophoblast (Syn) cells. The junctional zone, overlying the labyrinth zone, mainly contains the spongiotrophoblast (Sp), glycogen cells (GC), and the giant cells (GC). (C) Schematic representation of the chorionic villus in the human placenta demonstrating the cytotrophoblast (CTB), syncytiotrophoblast (Syn) cells, and the connective tissue constituting of macrophages (M) and the fetal vessels (FVs).

Figure 3

Schematic representation of trophoblast invasion in normal and pathogenic states. Trophoblast invasion for spiral artery remodeling is severely restricted in the decidua in PE while excessive trophoblast invasion in the myometrium and serosa is observed in placenta accreta, placenta increta, and placenta percreta. EVT: Extravillous trophoblast; CT: cytotrophoblast.

Figure 4

Super enhancers (SEs) and their putative role in placental physiology. Specific super enhancer-driven networks may have a significant role to play in events required for successful placentation. SE-driven networks can be associated with trophoblast development and differentiation, and trophoblast invasion of spiral arteries, which are important for vascular remodeling during pregnancy. Several SE-driven events may also be responsible for disease pathogenesis, specifically in placental diseases.