Vanden Oever Michael, Muldoon Daniel, Mathews Wendy, McElmurry Ron, Tolar Jakub
Department of Pediatrics, Division of Blood and Marrow Transplantation, University of Minnesota, Minneapolis, Minnesota, USA.
Department of Pediatrics, Division of Blood and Marrow Transplantation, University of Minnesota, Minneapolis, Minnesota, USA; Stem Cell Institute, University of Minnesota, Minneapolis, Minnesota, USA.
J Invest Dermatol. 2016 Oct;136(10):2013-2021. doi: 10.1016/j.jid.2016.05.115. Epub 2016 Jun 18.
Recessive dystrophic epidermolysis bullosa (RDEB) is a complex inherited skin disorder caused by loss-of-function mutations in the COL7A1 gene. 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 are needed. Currently, both posttranscriptional regulation of COL7A1 and the underlying causes of fibrosis in RDEB patients are poorly understood. Here, we describe a mechanism of regulation, to our knowledge previously unknown, by which micro RNA-29 (miR-29) regulates COL7A1 in a complex network: both directly through targeting its 3' untranslated region 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 transforming growth factor-β signaling. RDEB mice express high levels of transforming growth factor-β and significantly lower miR-29 compared with 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 profibrotic extracellular matrix collagens. Collectively, we identify miR-29 as an important factor in both regulating COL7A1 and inhibiting transforming growth factor-β-mediated fibrosis.
隐性营养不良性大疱性表皮松解症（RDEB）是一种复杂的遗传性皮肤病，由COL7A1基因的功能丧失突变引起。为了实现对这种疾病的有效治疗，既需要深入了解COL7A1的调控机制，也需要了解RDEB并发症的潜在本质。目前，人们对COL7A1的转录后调控以及RDEB患者纤维化的根本原因了解甚少。在此，我们描述了一种据我们所知此前未知的调控机制，即微小RNA-29（miR-29）在一个复杂网络中调控COL7A1：既直接通过靶向其3'非翻译区的两个不同种子区域，也间接通过靶向COL7A1基础表达所需的一种关键转录因子SP1。反过来，miR-29自身受SP1活性和转化生长因子-β信号传导的调控。与野生型群体相比，RDEB小鼠表达高水平的转化生长因子-β且miR-29显著降低。RDEB皮肤中miR-29的持续减少导致皮肤中miR-29靶基因的表达增加，包括促纤维化的细胞外基质胶原蛋白。总体而言，我们确定miR-29是调控COL7A1和抑制转化生长因子-β介导的纤维化的重要因素。
