miR-29 Regulates Type VII Collagen in Recessive Dystrophic Epidermolysis Bullosa

Abstract

Recessive dystrophic epidermolysis bullosa (RDEB) is a complex inherited skin disorder caused by loss-of-function mutations in the COL7A1 gene. In order for an effective treatment of this disorder to be realized, both a thorough understanding of the regulation of COL7A1 and an understanding of the underlying nature of the complications of RDEB is needed. Currently, both post-transcriptional regulation of COL7A1 and the underlying causes of fibrosis in RDEB patients are poorly understood. Here, we describe a previously unknown mechanism of regulation by which miR-29 regulates COL7A1 in a complex network: both directly through targeting its 3’ UTR at two distinct seed regions and indirectly through targeting an essential transcription factor required for basal COL7A1 expression, SP1. In turn miR-29 itself is regulated by SP1 activity and TGF-β signaling. RDEB mice express high levels of TGF-β and significantly lower miR-29 when compared to wild-type cohorts. The sustained decrease in miR-29 in RDEB skin leads to an increase of miR-29 target genes expressed in the skin, including pro-fibrotic extracellular matrix collagens. Collectively, we identify miR-29 as an important factor in both regulating COL7A1 and inhibiting TGF-β mediated fibrosis.

microRNA-29b mediates fibrotic induction of human xylosyltransferase-I in human dermal fibroblasts via the Sp1 pathway

“…Vanden Oever et al . 54 recently described type VII collagen downregulation in recessive dystrophic epidermolysis bullosa via miRNA-29b-mediated Sp1 repression. Comparable to the results gained here, SP1 mRNA expression was downregulated in a small but statistically significant extent by miRNA-29b transfection in dermal fibroblasts.…”

Epidermolysis Bullosa-Associated Squamous Cell Carcinoma: From Pathogenesis to Therapeutic Perspectives

“…Collagen VII (COL7) deficiency in recessive dystrophic epidermolysis bullosa (RDEB) skin and extracutaneous tissues favors squamous cell carcinoma (SCC) development. The figure summarizes literature findings on relevant pro-tumorigenic processes triggered by COL7 loss in RDEB keratinocytes, fibroblasts and lymphoid organs [42,44,49,52,57,58,59,61,62,63,64,67,84]. Red up arrows indicate increase/up-regulation, green down arrows indicate decrease/down-regulation.…”

“…Finally, microRNAs (miRNAs), a class of small non-coding RNAs with pleiotropic functions, are emerging as novel players in RDEB fibrosis [42,67], and potential regulators in tumor stroma cancerization. Deregulation of miRNAs expression and activity has been demonstrated to play a significant role in a variety of human diseases, including fibrotic skin disorders and SCC [68,69], but their involvement in RDEB and its complications are almost unexplored.…”

Tight junctions and their regulation by non-coding RNAs

“…MiRNAs are small single-stranded RNAs with lengths of 21-23 nucleotides that can bind to the 3' UTR of mRNAs and result in mRNAs silencing or degradation 104 , 105 . For example, miR-29 can participate in the pathogenesis of recessive dystrophic epidermolysis bullae by specifically silencing COL7A1 mRNA 106 . LncRNAs are long-stranded non-coding RNAs with lengths of 200-100,000 nucleotides that participate in the regulation of a variety of physiological and pathological processes 107 , 108 .…”