Retinoblastoma family of proteins and chromatin epigenetics: A repetitive story in a few LINEs

The retinoblastoma (RB) protein family in mammals is composed of three members: pRB (or RB1), p107, and p130. Although these proteins do not directly bind DNA, they associate with the E2F family of transcription factors which function as DNA sequence-specific transcription factors. RB proteins alter gene transcription via direct interference with E2F functions, as well as recruitment of transcriptional repressors and corepressors that silence gene expression through DNA and histone modifications. E2F/RB complexes shape the chromatin landscape through recruitment to CpG-rich regions in the genome, thus making E2F/RB complexes function as local and global regulators of gene expression and chromatin dynamics. Recruitment of E2F/pRB to the long interspersed nuclear element (LINE1) promoter enhances the role that RB proteins play in genome-wide regulation of heterochromatin. LINE1 elements are dispersed throughout the genome and therefore recruitment of RB to the LINE1 promoter suggests that LINE1 could serve as the scaffold on which RB builds up heterochromatic regions that silence and shape large stretches of chromatin. We suggest that mutations in RB function might lead to global rearrangement of heterochromatic domains with concomitant retrotransposon reactivation and increased genomic instability. These novel roles for RB proteins open the epigenetic-based way for new pharmacological treatments of RB-associated diseases, namely inhibitors of histone and DNA methylation, as well as histone deacetylase inhibitors.