Identification of miR-145 as a Key Regulator of the Pigmentary Process
Identification of miR-145 as a Key Regulator of the Pigmentary Process
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DOI：
10.1038/jid.2012.266
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发表时间：
2013-01-01
影响因子：
6.5
通讯作者：
Van Gele, Mireille J. L.
中科院分区：
文献类型：
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作者：
Dynoodt, Peter;Mestdagh, Pieter;Van Gele, Mireille J. L.
目前色素沉着过度的治疗通常与缺乏疗效和不良副作用有关。我们假设，基于microRNA（miRNA）的治疗可能会提供一个有吸引力的替代方案，专门针对黑素生成的关键基因。本研究的目的是鉴定干扰色素过程的miRNA并评估其功能作用。在涉及毛喉素和太阳模拟UV（ssUV）照射的三次连续处理后，对小鼠黑素细胞进行miRNA分析。16种miRNA被鉴定为在处理的melan-a细胞与未处理的细胞中差异表达。值得注意的是，检测到miR-145的15倍下调。miR-145在melan-a细胞中的过表达或下调分别揭示了Sox 9、Mitf、Tyr、Trpl、Myo 5a、Rab 27 a和Fscn 1的表达减少或增加。此外，荧光素酶报告基因测定证明了小鼠和人黑素细胞中miR-145对Myo 5a的直接靶向作用。对miR-145转染的人黑素细胞中的黑素体进行免疫荧光标记，显示黑素体的核周积聚，以及收获的细胞团块的额外色素减退。总之，这项研究已经建立了一个与毛喉素和ssUV治疗相关的miRNA签名。在调节miR-145表达后，主要色素沉着基因的显著下调或上调表明miR-145在调节黑素生成中的关键作用。Journal of Investigative Dermatology（2013）133，201-209; doi：10.1038/jid.2012.266; 2012年8月16日在线发表
The current treatments for hyperpigmentation are often associated with a lack of efficacy and adverse side effects. We hypothesized that microRNA (miRNA)-based treatments may offer an attractive alternative by specifically targeting key genes in melanogenesis. The aim of this study was to identify miRNAs interfering with the pigmentary process and to assess their functional role. miRNA profiling was performed on mouse melanocytes after three consecutive treatments involving forskolin and solar-simulated UV (ssUV) irradiation. Sixteen miRNAs were identified as differentially expressed in treated melan-a cells versus untreated cells. Remarkably, a 15-fold downregulation of miR-145 was detected. Overexpression or downregulation of miR-145 in melan-a cells revealed reduced or increased expression of Sox9, Mitf, Tyr, Trpl, Myo5a, Rab27a, and Fscn1, respectively. Moreover, a luciferase reporter assay demonstrated direct targeting of Myo5a by miR-145 in mouse and human melanocytes. Immunofluorescence tagging of melanosomes in miR-145-transfected human melanocytes displayed perinuclear accumulation of melanosomes with additional hypopigmentation of harvested cell pellets. In conclusion, this study has established an miRNA signature associated with forskolin and ssUV treatment. The significant down- or upregulation of major pigmentation genes, after modulating miR145 expression, suggests a key role for miR-145 in regulating melanogenesis. Journal of Investigative Dermatology (2013) 133, 201-209; doi:10.1038/jid.2012.266; published online 16 August 2012