Figure 1
(A) Role of XIST/RepA lncRNAs in X-chromosome inactivation. Initially, chromatin is relaxed and open to transcription, indicated by open grey circles representing active histone marks such as histone 3 lysine 4 dimethylation (H3K4m2) or H4 acetylation. Initiation of heterochromatinization requires transcription of RepA lncRNA, which recruits PRC2 protein (orange rhombus). This interaction is magnified to highlight the importance of knowing which regions of the lncRNAs and proteins play a role in it. In this case, the 7.5 tandem repeats of two stem-loop structures (5′ repeat A) seem to be important. They are also present in the XIST transcript and interact with SUZ12 protein. Thus, a switch between activatory and repressive histone marks begins, resulting in trimethylation of H3K27. Finally, XIST lncRNA spreads along the X chromosome and propagates PRC2 silencing throughout the X chromosome. (B) Role of DBE-T transcript in FSHD disease. In healthy individuals, DNA hypermethylation of 4q35 locus is prevalent and there is generalized PRC2 coating over the chromatin strands. Open red circles represent H3K27m3. This is possible due to the many tandem repeat copies of the D4Z4 macrosatellite, which also inhibits DBE-T transcription. This scenario averts DUX4 gene transcription from the final D4Z4 repeat and other myopathic genes (ANT1 or FRG1/2), preventing the development of the FSHD syndrome. If the number of D4Z4 repeats is reduced below 11 copies, the epigenetic scenario changes dramatically, decreasing levels of DNA methylation, histone-repressive marks (e.g., H3K27m3; open red circles), and PRC2 attachment along the chromatin (orange polygons). However, this permissive environment enables the transcription of DBE-T lncRNA, which specifically recruits the ASH1L protein belonging to the Trx group. This is responsible for histone 3 lysine 36 dimethylation (H3K36m2) and histone 3 lysine 4 trimethylation (H3K4m3) activatory marks (open grey circles).
