miR-29c-3p promotes alcohol dehydrogenase gene cluster expression by activating an ADH6 enhancer
miR-29c-3p promotes alcohol dehydrogenase gene cluster expression by activating an ADH6 enhancer
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miR-29c-3p 通过激活 ADH6 增强子促进乙醇脱氢酶基因簇表达。
DOI：
10.1016/j.bcp.2022.115182
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发表时间：
2022-07-30
影响因子：
5.8
通讯作者：
Yu, Dianke
中科院分区：
文献类型：
--
作者：
Chen, Ningning;Luo, Jiao;Yu, Dianke
乙醇脱氢酶（ADH）在酒精代谢和酒精毒性中起着重要作用，但对microRNA介导的ADH基因簇调控知之甚少。在这里，我们发现miR-29 c通过靶向ADH 6基因内的增强子元件激活ADH基因簇转录。miR-29 c在酒精性肝病中的差异表达随后的生物化学和分子证据表明，miR-29 c增加了ADH 6 mRNA和蛋白水平，而不影响ADH 6转录物的稳定性。进一步的证据表明，外源性miR-29 c易位到细胞核中，然后非常规地结合ADH 6基因内的增强子元件。荧光素酶报告基因分析和染色质免疫沉淀数据表明，miR-29 c激活了增强子，并增加了RNA聚合酶II在ADH 1A、ADH 1B、ADH 1C、ADH 4和ADH 6启动子区域的富集。最后，外源性miR-29 c转染促进ADH基因簇的ADH 1A、ADH 1B、ADH 1C和ADH 4前体mRNA和mRNA转录物的表达。总之，我们的数据表明，miR-29 c可能是一种新的表观遗传调节剂参与ADH基因簇的激活。
Alcohol dehydrogenases (ADHs) play vital roles in alcohol metabolism and alcohol toxicity, yet little is known about microRNA-mediated regulation of the ADH gene cluster. Here, we showed that miR-29c activated ADH gene cluster transcription by targeting an enhancer element within the ADH6 gene. miR-29c is differentially expressed in alcoholic liver disease. Following biochemical and molecular evidence demonstrated that miR-29c increased ADH6 mRNA and protein levels without affecting the stability of the ADH6 transcript. Further evidence showed that exogenous miR-29c translocated into the nucleus and then unconventionally bound an enhancer element within the ADH6 gene. Luciferase reporter assay and chromatin immunoprecipitation data indicated that miR-29c activated the enhancer and increased the enrichment of RNA polymerase II at the promoter regions of ADH1A, ADH1B, ADH1C, ADH4, and ADH6. Finally, exogenous miR-29c transfection promoted the expression of ADH1A, ADH1B, ADH1C, and ADH4 pre-mRNA and mRNA transcripts from the ADH gene cluster. In conclusion, our data suggest that miR-29c might be a novel epigenetic regulator involved in ADH gene cluster activation.