A repetitive elements perspective in Polycomb epigenetics

Abstract

Repetitive elements comprise over two-thirds of the human genome. For a long time, these elements have received little attention since they were considered non-functional. On the contrary, recent evidence indicates that they play central roles in genome integrity, gene expression, and disease. Indeed, repeats display meiotic instability associated with disease and are located within common fragile sites, which are hotspots of chromosome re-arrangements in tumors. Moreover, a variety of diseases have been associated with aberrant transcription of repetitive elements. Overall this indicates that appropriate regulation of repetitive elements’ activity is fundamental. Polycomb group (PcG) proteins are epigenetic regulators that are essential for the normal development of multicellular organisms. Mammalian PcG proteins are involved in fundamental processes, such as cellular memory, cell proliferation, genomic imprinting, X-inactivation, and cancer development. PcG proteins can convey their activity through long-distance interactions also on different chromosomes. This indicates that the 3D organization of PcG proteins contributes significantly to their function. However, it is still unclear how these complex mechanisms are orchestrated and which role PcG proteins play in the multi-level organization of gene regulation. Intriguingly, the greatest proportion of Polycomb-mediated chromatin modifications is located in genomic repeats and it has been suggested that they could provide a binding platform for Polycomb proteins. Here, these lines of evidence are woven together to discuss how repetitive elements could contribute to chromatin organization in the 3D nuclear space.

Facioscapulohumeral Muscular Dystrophy As a Model for Epigenetic Regulation and Disease

“…DNA repeats can play regulatory roles for nearby genes in cis and in trans, express regulatory non-coding RNAs (ncRNAs), and, as is the case for D4Z4, encode protein-coding genes within the repeat (21,28,46,52,155). Numerous candidate genes have been proposed for mediating FSHD pathogenesis based on differential expression between FSHD-affected and healthy myogenic cells, with little consensus (2,26,27,43,50,86,125,129) (71).…”

The significance of Hox gene collinearity

“…3) (Sha and Boyer, 2009). Trx-bound expressible chromatin is also marked by a loose structure and trimethylation of lysine 4 on histone 3 (H3K4me3), whereas Pc-bound repressed chromatin is marked by a compact structure and trimethylation of lysine 27 on histone structures within the cell nucleus (Casa andGabellini, 2012, Lanzuolo et al, 2007). Similarly, the Trx-bound genes, when active, occupy discreet regions called 'transcription factories' (Casa & Gabellini, 2012;Lanzuolo et al, 2007).…”

“…Trx-bound expressible chromatin is also marked by a loose structure and trimethylation of lysine 4 on histone 3 (H3K4me3), whereas Pc-bound repressed chromatin is marked by a compact structure and trimethylation of lysine 27 on histone structures within the cell nucleus (Casa andGabellini, 2012, Lanzuolo et al, 2007). Similarly, the Trx-bound genes, when active, occupy discreet regions called 'transcription factories' (Casa & Gabellini, 2012;Lanzuolo et al, 2007). It is suggested that it is only within Pc hubs and transcription factories that there is sufficient concentration of regulatory proteins (Pc-or Trx-complex components and transcription factors) to ensure efficient Hox gene repression or activation Karch, 2009, Sutherland andBickmore, 2009).…”

Epigenetics and Human Disease

“…The 4q35 region normally displays features typical of heterochromatin, such as DNA methylation, histone hypoacetylation H3K9 methylation, HP1g and cohesin binding, but also methylation of H3K27, which is more typical of developmentally regulated genes (reviewed in Casa and Gabellini 2012). It is presumed that D4Z4 repeats are the trigger for heterochromatin formation when the range of repeats is 11 -150.…”