Polycomb group proteins are key regulators of keratinocyte function

Abstract

The Polycomb group (PcG) proteins are epigenetic suppressors of gene expression that function through modification of histones to change chromatin structure and modulate gene expression and cell behavior. Recent studies show that PcG proteins are expressed in epidermis, that their levels change during differentiation and in disease states, and that PcG expression is regulated by agents that influence cell proliferation and survival. The results indicate that PcG proteins regulate keratinocyte cell-cycle progression, apoptosis, senescence, and differentiation. These proteins are expressed in progenitor cells, in the basal layer, and in suprabasal keratinocytes, and the level, timing, and distribution of expression suggest that the PcG proteins have a central role in maintaining the balance between cell survival and death in multiple epidermal compartments. Additional studies indicate an important role in skin cancer progression.

Figure 1. Polycomb complexes

The PRC2 complex consists of four core proteins including RBAP48, SUZ12, EZH2, and EED. EZH2 is the methyltransferase responsible for methylation of lysine 27 of histone H3, and this methylation activity resides in the SET domain. Interaction with other proteins in the complex is required for EZH2 activity. PHF1 is a polycomb protein that is not part of the core complex, but functions to increase EZH2 activity and is also involved in PRC2 complex interaction with chromatin. The PRC1 complex comprises four core proteins including RING1B, CBX, Bmi-1, and PH1. RING1B is an E3 ubiquitin ligase that specifically ubiquitinylates lysine 119 of histone H2A. Bmi-1 interacts directly with RING1B to enhance Ring1B ubiquitin ligase activity. CBX encodes the domain (chromodomain, CD) responsible for anchoring the PRC1 complex to methylated lysine 27 of histone H3.

Figure 2. Simplified description of PcG regulation of transcription

The PRC2 complex is recruited to chromatin, and the Ezh2 protein of this complex, a histone methyltransferase, catalyzes formation of H3K27me3 through its SET catalytic site. H3K27me3 then functions as a binding site for the CBX protein of the PRC1 complex. CBX encodes a chromodomain site that has a high affinity for H3K27me3. The interaction of CBX with H3K27me3 anchors the PRC1 complex to chromatin, and the RING1B subunit of the complex, an E3 ubiquitin ligase, catalyzes formation of H2A-K199-ub. Ultimately these events lead to chromatin folding and compaction and cessation of transcription. The dashed line indicates binding interaction and the solid lines indicate covalent modifications.