Polycomb repressive 2 complex-Molecular mechanisms of function

Abstract

Numerous molecular processes conduct epigenetic regulation of protein transcription to maintain cell specification. In this review, we discuss molecular mechanisms of the Polycomb group of proteins and its enzymatic role in epigenetics. More specifically, we focus on the Polycomb repressive complex 2 (PRC2) and the effects of its repressive marker. We have compiled information regarding the biological structure and how that impacts the stability of the complex. In addition, we examined functions of the individual core proteins of PRC2 in relation to the accessory proteins that interact with the complex. Lastly, we discuss the implications of unregulated and downregulated PRC2 activity in Alzheimer's disease and cancer and possible methods of treatment related to PRC2 regulation.

Keywords: AEBP2; Alzheimer's disease; EED; EZH1/2; JARID2; RBBP4/7; SUZ12; cancer; polycomb group, PcG; polycomb repressive complex 2, PRC2.

Figure 1

Surface image of PRC2 complex (based on the crystal structure with the PDB ID 6c23). The core PRC2 complex contains three primary subunits: EED, SUZ12, and EZH2. Complex interacts with AEBP2, PLC1‐3, RBBP4, RBB7, and JARID2 (in creatine phosphokinase (CPK) presentation bound to EED subunit). The interactions between the complex and its accessory proteins constitute the complete molecular and catalytic function of the core complex as well as facilitate recruitment. In the inset the scheme from the open access article,21 is used. Color scheme: Pink—inhibitor (carbon C), blue—nitrogen N, red—oxygen O; cyan—EED; purple—EZH2 (chains K and C); green—SUZ12 (chains A, M, and Q); dodger‐blue—RBBP4, magenta—AEBP2, silver—SUZ12 (chain Z); yellow—JUMONJI (chain E); gold—JUMONJI (chain B).

Figure 2

Diagram of polycomb repressive complex 2 (PRC2) suppression of neurodegenerative transcription process in neurons. The PRC2 complex is composed of three core subunits: suppressor of zeste 12 (SUZ12), embryonic ectoderm development (EED), and enhancer of zeste 2 (EZH2). The primary function of the EZH2 protein is to catalyze the trimethylation of lysine 27 on histone H3 (H3K27). This modification of H3K27 results in newly formed H3K27me3 that leads to chromatin compaction and prevents transcription units from accessing the transcription start site (TSS) of the gene sequence and thus silencing neurodegenerative genes. Alzheimer's related genes, such as APP, Wt1, and PSEN1, have shown potential correlations with H3K27me3 through either hypomethylation of hypermethylation in the AD brain. More significantly is that this histone modification has been exhibited to be preserved during cell division and is thus essential in maintaining the silencing of these harmful genes. Trimethylation of H3K27 was also shown to be related to cancer.12, 21, 27

Figure 3

Diagram of PRC2 recruitment to CpG island (CGI) on an unmethylated strand of DNA. It has been shown that DNA‐binding domains (DBD) and certain transcription factors (TFs) can mediate the recruitment of polycomb group (PcG) complexes, such as PRC2, to CGIs with CG‐rich regions. Once recruited, the complex stabilizes itself with the assistance from its accessory proteins and begins to carry out the methylation process on target genes. This method of recruitment provides insight toward genomic locations of PRC2 attachment as well as enabling scientific predictions due to the CGI attachment tendency. Reproduced from the open access article.21

Figure 4

Inhibitors bound to PRC2 complex domains. Color scheme: pink—inhibitor (carbon C), blue—nitrogen N, red—oxygen O; cyan—EED; purple—EZH2; green—SUZ12; salmon—JARID2; light‐blue—zinc Zn. (a) Inhibitor GSK126 (C31H38N6O2) bound to EZH2 domain of PRC2 (based on crystal structure PDB ID 5wg6). (b) Inhibitor CPI‐1205 (C28H36F2N4O3) bound to EZH2 domain of PRC2 (based on crystal structure PDB ID 5ls6). (c) Inhibitor EED396 (C25H24N3O⁺) bound to EED domain of PRC2 (based on crystal structure PDB ID 5h13).

Figure 5

Two‐dimensional structures of important PRC2 complex inhibitors. (a) PRC2 complex inhibitors binding to EZH2 protein. (b) PRC2 complex inhibitors binding to EED protein.