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

Abstract

Embryonic development is a highly intricate and complex process. Different regulatory mechanisms cooperatively dictate the fate of cells as they progress from pluripotent stem cells to terminally differentiated cell types in tissues. A crucial regulator of these processes is the Polycomb Repressive Complex 2 (PRC2). By catalyzing the mono-, di-, and tri-methylation of lysine residues on histone H3 tails (H3K27me3), PRC2 compacts chromatin by cooperating with Polycomb Repressive Complex 1 (PRC1) and represses transcription of target genes. Proteomic and biochemical studies have revealed two variant complexes of PRC2, namely PRC2.1 which consists of the core proteins (EZH2, SUZ12, EED, and RBBP4/7) interacting with one of the Polycomb-like proteins (MTF2, PHF1, PHF19), and EPOP or PALI1/2, and PRC2.2 which contains JARID2 and AEBP2 proteins. MTF2 and JARID2 have been discovered to have crucial roles in directing and recruiting PRC2 to target genes for repression in embryonic stem cells (ESCs). Following these findings, recent work in the field has begun to explore the roles of different PRC2 variant complexes during different stages of embryonic development, by examining molecular phenotypes of PRC2 mutants in both in vitro (2D and 3D differentiation) and in vivo (knock-out mice) assays, analyzed with modern single-cell omics and biochemical assays. In this review, we discuss the latest findings that uncovered the roles of different PRC2 proteins during cell-fate and lineage specification and extrapolate these findings to define a developmental roadmap for different flavors of PRC2 regulation during mammalian embryonic development.

Keywords: H2AK119ub; H3K27me3; Polycomb; embryogenesis; lineage commitment; pluripotency.

Figure 1

Schematic overview of the different Polycomb group proteins.

Figure 2

Feedback regulatory loops between activating and repressive complexes. Dashed arrow lines represent the feedback and cooperation between PRC1 and PRC2 variant complexes.

Figure 3

Differences in pattern of Polycomb group protein expression and their embryonic loss-of-function phenotypes. Embryo pictures reprinted from “Mouse Development”, by BioRender.com (accessed on 15 July 2022). (2022). Retrieved from https://app.biorender.com/biorender-templates (accessed on 15 July 2022).

Figure 4

Developmental roadmap charting Polycomb function and involvement at different key lineage decision steps.

Figure 5

Modern approaches and technological advances in studying Polycomb functional biology. With illustrations reprinted from “Petri dish with cells”, “3D organoids”, “Single-cell RNA seq cluster graph”, and “10X Genomics” by BioRender.com (accessed on 15 July 2022). (2022). Retrieved from https://app.biorender.com/biorender-templates (accessed on 15 July 2022).