miR-181a/b及其宿主基因lncRNA MIR181A2HG协同调控角质形成细胞异常增殖与分化的机制

The study on the regulation of keratinocyte aberrant proliferation and differentiation has been a crucial topic for psoriasis pathological mechanism research. Our previous study found that: 1)the expression of miR-181a/b and its host gene MIR181A2HG are decreased in psoriasis lesions versus normal skin; 2) overexpression and knockdown assay revealed miR-181a/b and MIR181A2HG play similar functions in the regulation of keratinocyte proliferation and differentiation, and they all inhibit the aberrant activation, promote the differentiation of keratinocyte, and show a synergistic effect; 3) MIR181A2HG functions independently of miR181a/b. On this basis, the role of MIR181A2HG and miR-181a/b in the regulation of keratinocyte aberrant proliferation and differentiation will be further confirmed through overexpression and RNA interference methods. By using macroarray, luciferase reporter assay, pulldown, mass spectrometry, RIP and EMSA, the mechanism of MIR181A2HG and miR-181a/b regulating keratinocyte proliferation and differentiation and their possible synergistic mechanisms will be revealed. This study will further provide theoretical clues for understanding the mechanism of aberrant proliferation and differentiation of psoriatic keratinocytes.

研究角质形成细胞的异常增殖与分化调控一直是银屑病病理机制研究的一项重要课题。我们前期研究发现：1）银屑病患者皮损处较正常人miR-181a/b及其宿主基因MIR181A2HG表达降低；2）过表达和干扰实验显示miR-181a/b与MIR181A2HG在角质形成细胞增殖分化中发挥相似的功能，皆能够抑制角质形成细胞的异常活化，促进角质形成细胞的分化，且呈现出协同效应；3）MIR181A2HG发挥作用不依赖于miR181a/b。在此基础上，拟通过过表达和干扰技术进一步证实MIR181A2HG和miR-181a/b在角质形成细胞异常增殖分化调控中的作用；并结合基因芯片、荧光素酶报告基因分析、pulldown、质谱、RIP和EMSA等多种技术手段进一步明确调控方式及其协同机制，以期为银屑病角质形成细胞异常增殖与分化的机制理解提供新的线索。

研究角质形成细胞的异常增殖与分化调控一直是银屑病病理机制研究的一项重要课题。课题组前期研究发现，MIR181A2HG 基因簇来源的 ncRNA （MIR181A2HG和miR-181a/b）在银屑病皮损区低表达并参与银屑病角质形成细胞的增殖和分化调控。本研究拟通过过表达和干扰技术进一步证实 MIR181A2HG 和miR-181a/b 在角质形成细胞异常增殖分化调控中的作用，并结合pulldown、质谱分析、RIP 和生物信息学分析等多种技术手段进一步阐明调控方式及其协同机制。研究发现，MIR181A2HG和miR-181a/b在银屑病皮损处低表达进而促进角质形成细胞增殖，抑制其分化。MIR181A2HG在核内外皆有分布，可能通过结合SRSF1发挥核内调控作用，通过miR-223-3p靶向SOX6发挥核外调控作用。miR-181a/b可能通过靶向MELK和CCNB1发挥增殖调控作用。MIR181A2HG与miR-181a/b存在协同作用，可能通过SRSF1、SOX6、MELK、CCNB1等发挥作用，但确切的下游分子机制有待进一步研究。研究结果为银屑病角质形成细胞异常增殖与分化的机制理解提供线索。

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