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. 2015 Mar 26;24(12):3457–3471. doi: 10.1093/hmg/ddv096

Figure 6.

Figure 6.

Model of GAA repeat-mediated FXN repression and the repressive role of NL in FXN transcriptional impairment. The euchromatic state of normal FXN alleles allows physiological levels of expression (I). Expanded GAA repeats trigger R-loop formation and locally recruit HP1 (13), G9a methyltransferase (6) and class I (8) and III (27) HDACs, causing epigenetic changes that contribute to transcriptional dysregulation (II). These GAA expansion-mediated structural and epigenetic changes may lead to FXN relocation to the NL—a location known to be a generally repressive environment and enriched in HDAC and histone methyltransferase activity—where further repression (III) and silencing (IV) occur. ONM, outer nuclear membrane; INM, inner nuclear membrane; CM, cell membrane.