Targeting Polycomb systems to regulate gene expression: modifications to a complex story

Abstract

Polycomb group proteins are transcriptional repressors that are essential for normal gene regulation during development. Recent studies suggest that Polycomb repressive complexes (PRCs) recognize and are recruited to their genomic target sites through a range of different mechanisms, which involve transcription factors, CpG island elements and non-coding RNAs. Together with the realization that the interplay between PRC1 and PRC2 is more intricate than was previously appreciated, this has increased our understanding of the vertebrate Polycomb system at the molecular level.

Figure 1. Getting polycomb repressive complexes to chromatin.

a | Locus-specific targeting of polycomb repressive complexes. PRC1 and PRC2 can associate with DNA binding transcription factors (top-left), such as RUNX1 and REST, which guide these complexes to chromatin. Similarly, interactions with long non-coding RNAs such as Xist function in chromosome- and locus-specific targeting of polycomb complexes (bottom-left). The chromatin remodelling protein ATRX may remodel the structure of Xist to achieve interaction with PRC2. Following recruitment to chromatin, PRC1 catalyses ubiquitylation of H2AK119 and PRC2 catalyses trimethylation of H3K27, as indicated by rounded arrows. The square arrows indicate transcription start sites. b | Generic targeting of polycomb repressive complexes to gene regulatory elements. A variant PRC1 complex containsthe KDM2B protein. KDM2B has a zinc-finger CxxC DNA binding domain (red area) that specifically recognizes non-methylated CpG dinucleotides. This allows KDM2B to bind at CpG islands genome-wide, and contributes to PRC1 occupancy at these elements (top-right). PRC2 interacts with nascent RNA polymerase II (Pol II) transcripts at 5’-ends of genes, which may provide a mechanism to maintain repression at silent genes following stochastic transcription initiation events. Alternatively, at active genes, interaction of PRC2 with nascent RNA may constrain the catalytic activity of PRC2 and protect against polycomb-mediated repression (middle-right). A subset of PRC2 complexes contain PCL proteins which bind to H3K36me3, a modification associated with active transcription. This may enable PRC2 to bind at, or spread into, previously transcribed regions, catalysing H3K27me3 at these regions.

Figure 2. Beyond simple recruitment to more complex interactions.

a | In the ‘hierarchical’ model of polycomb complex function, PRC2 first binds to chromatin and places H3K27me3. It is then proposed that H3K27me3 is recognized by chromobox (CBX) proteins, which are a subunit of canonical PRC1 complexes, thereby allowing PRC1 to bind and mono-ubiquitylate H2AK119. b | In the ‘Alternative’ model for polycomb recruitment, the initial event is the binding of variant PRC1 complexes (which contain RYBP instead of CBX) to chromatin. PRC1 then catalyses the mono-ubiquitylation of H2AK119, independently of PRC2 activity and H3K27me3. The H2AK119ub1 modification then promotes the recruitment of PRC2, possibly via direct recognition of H2AK119ub1 by the AEBP2-JARID2-PRC2 complex, and placement of the H3K27me3 mark. c | PRC1 complexes functionally segregate into ‘canonical’ complexes that contain chromobox (CBX2/4/6/7/8) and polyhomeotic (PHC1/2/3) proteins, and a series of ‘variant’ complexes that contain RYBP (or the closely related YAF2 protein) and interact with proteins that are unique to individual variant PRC1 complexes (note that only selected proteins are shown here). Under some conditions the PRC2 subunit EED may interact with a CBX-containing canonical PRC1 complex (dashed arrow). d | A model for the propagation of polycomb domains.Within the core PRC2 complex, the EED subunit is able to recognise H3K27me3 via its WD40 repeat domain. This interaction potentially recruits PRC2 to sites of pre-existing H3K27me3, as well as stimulating the enzymatic activity of PRC2. The EED-H3K27me3 interaction may facilitate spreading of H3K27me3 domains (left panel, dashed arrows) or copying of H3K27me3 onto newly incorporated histones (right panel, blue nucleosomes) during DNA replication, thereby stably propagating H3K27me3 domains in actively dividing cells.

Figure 3. Polycomb systems and gene regulation.

a | An instructive model for polycomb complex-mediated silencing would posit that newly recruited polycomb complexes lead to polycomb chromatin domain formation, which then directs repression of transcription by RNA Polymerase II (Pol II) at the associated gene. b | A responsive model would posit that polycomb complexes constantly ‘sample’ chromatin at regulatory elements via generic targeting modalities in order to respond to the transcriptional state of the associated gene. Transcriptional cessation would lead to the subsequent establishment of polycomb chromatin domains that protect against low-level or stochastic reactivation signals. However, in response to active transcription, the presence of Pol II or other features of transcriptional initiation would block polycomb domain establishment.