A Long ncRNA Links Copy Number Variation to a Polycomb/Trithorax Epigenetic Switch in FSHD Muscular Dystrophy

Abstract

SummaryRepetitive sequences account for more than 50% of the human genome. Facioscapulohumeral muscular dystrophy (FSHD) is an autosomal-dominant disease associated with reduction in the copy number of the D4Z4 repeat mapping to 4q35. By an unknown mechanism, D4Z4 deletion causes an epigenetic switch leading to de-repression of 4q35 genes. Here we show that the Polycomb group of epigenetic repressors targets D4Z4 in healthy subjects and that D4Z4 deletion is associated with reduced Polycomb silencing in FSHD patients. We identify DBE-T, a chromatin-associated noncoding RNA produced selectively in FSHD patients that coordinates de-repression of 4q35 genes. DBE-T recruits the Trithorax group protein Ash1L to the FSHD locus, driving histone H3 lysine 36 dimethylation, chromatin remodeling, and 4q35 gene transcription. This study provides insights into the biological function of repetitive sequences in regulating gene expression and shows how mutations of such elements can influence the progression of a human genetic disease.

Genome-Wide Analysis Uncovers Regulation of Long Intergenic Noncoding RNAs in Arabidopsis

“…Emerging evidence supports the view that lincRNAs play important roles in many fundamental biological processes (Hekimoglu and Ringrose, 2009;Chen and Carmichael, 2010;Tsai et al, 2010; K.C. Cabianca et al, 2012). Consistent with this view, knockdown of a group of lincRNAs in mouse embryonic stem cells disrupted pluripotency and/or altered expression levels of differentiation markers (Guttman et al, 2011).…”

“…Consistent with this view, knockdown of a group of lincRNAs in mouse embryonic stem cells disrupted pluripotency and/or altered expression levels of differentiation markers (Guttman et al, 2011). In addition, genetic mutations of human lincRNAs have been associated with diseases and pathophysiological conditions (Gupta et al, 2010;Hu et al, 2011;Zhu et al, 2011;Cabianca et al, 2012).…”

The activatory long non-coding RNA DBE-T reveals the epigenetic etiology of facioscapulohumeral muscular dystrophy

“…In contrast to the aforementioned lncRNAs, and highlighting one of the most significant discoveries of Cabianca et al [1], DBE-T is an example of a lncRNA that interacts with the PcG antagonist protein complex, the Trithorax group (Trx). Therefore, the DBE-T transcript is defined as a lncRNA that coordinates the activation of certain PRC2 target-repressed genes, such as DUX4, at the 4q35 locus ( Figure 1B).…”

“…A recent paper published in Cell has proposed a new model that sets out the epigenetic basis of FSHD disease, and offers new and interesting discoveries from research in this area. Cabianca et al [1] have turned their attention to a molecular world that has been poorly investigated until now. They describe a novel, long non-coding RNA (lncRNA), known as DBE-T, arising from repetitive sequences, that plays an important role in human disease through its involvement in gene regulation.…”

“…Wang et al [10] described the first activatory lncRNA in 2011: HOTTIP, a long intergenic non-coding RNA (lincRNA) involved in the production of HOXA genes. Cabianca et al [1] have identified the first lncRNA linked to the Trithorax activation complex in relation to a particular disorder. A long list of lncRNAs involved in human disease lies ahead of us to be discovered [11].…”