Fig. 2

The main function of CBXs family proteins. (A) CBX 2/4/6/7/8, integral components of the canonical Polycomb Repressive Complex 1 (cPRC1), collaborate with Polyhomeotic proteins (PHC1/2/3) and SCM proteins (SCML1/2 or SCMH1) to form a complex around the catalytic core composed of RING1A/B and Polycomb group RING finger proteins (PCGF2/4). These CBX proteins serve as histone methylation readers, specifically recognizing the methylation of histone H3 at lysine K27 (H3K27me3) mark catalysed by Polycomb repressive complex 2 (PRC2), which mainly contains four core subunits: enhancer of zeste homolog 1/2 (EZH1/2), embryonic ectoderm development (EED), suppressor of zeste 12 (SUZ12), and retinoblastoma protein-associated proteins 46/48 (RBAP46/48). The H3K24/K36 demethylase KDM2B directs cPRC1 to genomic loci pre-marked by PRC2. Within this complex, the RING proteins catalyse the ubiquitination of histone H2A at lysine 119 (H2AK119ub1), leading to chromatin compaction, transcriptional repression, and the downregulation of target gene expression. This mechanism is recognized as the classical PRC1-dependent pathway. (B) HP1 contains the amino terminal chromatin domain (CD) and the carboxyl-terminal chromatin shadow domain (CSD), which are connected by a hinge domain (H) that imparts nucleic acid binding activity. CD acts as a “reader” and is responsible for recognizing the methylated histone H3 at lysine K9 (H3K9me2/3) and interacting with the methylated histone tail-specific CHD, and the higher the H3K9me2/H3K9me3 level, The affinity between HP1 and methylated histone tail CHD was stronger. CSD contains homologous and heterodimer domains, and is mainly responsible for forming a dimerization interface for recruiting specific ligands, recruiting SUV39H1 (an inhibitor of H3K9 methyltransferase) to methylate neighbouring nucleosomes, creating new binding sites for other HP1s to form a positive feedback loop, leading to the formation of inhibitory H3K9me3 markers along specific chromosome regions, with a large number of proteins recruited and inserted into genes that cannot be transcribed, thus inducing heterochromatin formation and spread, resulting in chromatin structure compression and gene silencing.