UVB诱导MALAT1调控MITF表达促皮肤色素沉着的作用及机制研究

MITF is a key factor regulating melanin synthesis and transfer. It has been confirmed that the ultraviolet ray can induce skin pigmentation by promoting MITF. However, the pathogenic mechanisms remain incompletely understood. We found elevated MALAT1 expression in tanning skin tissue and UVB-irradiated melanocytes. Our previous study found the melanin content decreased after inhibiting the MALAT1 expression in melanocytes. The gene chip experiment on screening mRNAs revealed that the MITF expression was downregulated after inhibiting the MALAT1 expression. Preliminary study showed that UVB-induced MALAT1 may regulate melanin synthesis and transfer in melanocytes by regulating MITF expression. Recent studies have found that MALAT1 can upregulate gene expression by inhibiting DNA methylation level. And the MITF expression is regulated by the DNA methylation level. So, we suggest that “UVB→MALAT1→MITF promoter demethylation→MITF→melanin synthesis and transfer” regulation axis exists. In this study, we tend to prove that MALAT1 can promote the UVB-induced melanin synthesis and transfer in melanocytes by regulating MITF expression. And we will also explore the specific mechanism of MALAT1 regulating MITF expression. This study will provide novel targets and new ideas for treatment of hyperpigmented skin diseases.

MITF是调控黑素合成及转运的关键分子，目前已证实紫外线可通过促进MITF表达诱导皮肤色素沉着，但紫外线促进MITF表达的机制尚未完全阐明。我们发现长期日晒的皮肤组织及UVB照射后的黑素细胞中长链非编码RNA MALAT1表达上调。预实验发现抑制MALAT1表达后，黑素细胞黑素含量下调；基因芯片筛查发现抑制MALAT1表达后，黑素细胞MITF表达下调。提示UVB诱导的MALAT1可通过调控MITF的表达影响黑素的合成及转运。新近研究发现MALAT1可抑制DNA甲基化水平上调基因的表达，且MITF表达受DNA甲基化调控。因此我们提出“UVB→MALAT1→MITF启动子低甲基化→MITF→黑素合成及转运”轴存在的假说。本研究拟验证MALAT1通过调控MITF表达介导UVB诱导的黑素合成及转运的作用，并探讨MALAT1调控MITF表达的具体机制，为色素沉着过度性皮肤病的治疗提供新靶点及新思路。

紫外线（UV）可通过影响miRNAs、蛋白泛素化/磷酸化等表观遗传学的方式诱导黑素细胞MITF的表达，进而促进黑素合成和转运。但lncRNA和DNA甲基化修饰作为表观遗传学调控的重要手段，在调节UV诱导的皮肤色素沉着中作用并不明确。本研究主要探索了lncRNA MALAT1参与UVB诱导的黑素生成，并通过DNMT1调控MITF表达的作用和机制。研究从临床样本、黑素生成细胞表型、分子指标等多角度证实了MALAT1对黑素生成的促进作用。此外通过数据库筛选及功能实验，发现MALAT1可能是通过靶向miR-152发挥作用。同时证实DNA甲基化酶 DNMT1参与MALAT1 对黑素生成的调控，并能拮抗 MALAT1诱导的色素生成。研究进一步夯实了lncRNA和DNA甲基化在黑素生成中的调控作用，并发现MALAT1与DNA甲基化修饰之间具有紧密的关联。当前成果为继续深挖表观遗传学在皮肤色素代谢异常性疾病中的角色提供了新的依据，并有望为临床诊治带来新的思路。