Small molecules capable of activating DNA methylation-repressed genes targeted by the p38 mitogen-activated protein kinase pathway
Small molecules capable of activating DNA methylation-repressed genes targeted by the p38 mitogen-activated protein kinase pathway
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能够激活 DNA 甲基化的小分子 - p38 丝裂原激活蛋白激酶通路靶向的抑制基因
DOI：
10.1074/jbc.ra117.000757
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发表时间：
2018-05-11
影响因子：
4.8
通讯作者：
Zhang, Zhuqiang
中科院分区：
文献类型：
--
作者：
Li, Xiang;Shang, Erchang;Zhang, Zhuqiang
通过表观遗传修饰（如DNA甲基化）调节基因表达对于发育和疾病过程（包括细胞分化和癌症发展）至关重要。被DNA甲基化抑制的基因可以被靶向DNA甲基转移酶、组蛋白脱乙酰酶和其他调节因子的各种化合物去抑制。然而，可能存在一些促进DNA甲基化介导的基因沉默的额外的未知机制。因此，可以抵消不受DNA甲基转移酶或组蛋白脱乙酰酶调节的表观遗传抑制作用的化学试剂可能具有研究兴趣。在这里，我们报告了一个高通量筛选的结果，使用308，251个成员的化学文库，以确定有效的小分子，去抑制由DNA甲基化沉默的EGFP报告基因。鉴定了七种命中化合物，其不直接靶向大量DNA甲基化或组蛋白乙酰化。分析这些化合物对内源性基因表达的影响，我们发现这些化合物中的三种（化合物LX-3、LX-4和LX-5）选择性地激活p38促分裂原活化蛋白激酶（MAPK）途径，并抑制被DNA甲基化抑制的内源性基因的子集。p38通路的选择性激动剂一直缺乏，我们的研究现在提供了关键的化合物，研究这一途径和p38 MAPK靶向基因抑制DNA甲基化。
Regulation of gene expression by epigenetic modifications such as DNA methylation is crucial for developmental and disease processes, including cell differentiation and cancer development. Genes repressed by DNA methylation can be derepressed by various compounds that target DNA methyltransferases, histone deacetylases, and other regulatory factors. However, some additional, unknown mechanisms that promote DNA methylation–mediated gene silencing may exist. Chemical agents that can counteract the effects of epigenetic repression that is not regulated by DNA methyltransferases or histone deacetylases therefore may be of research interest. Here, we report the results of a high-throughput screen using a 308,251-member chemical library to identify potent small molecules that derepress an EGFP reporter gene silenced by DNA methylation. Seven hit compounds were identified that did not directly target bulk DNA methylation or histone acetylation. Analyzing the effect of these compounds on endogenous gene expression, we discovered that three of these compounds (compounds LX-3, LX-4, and LX-5) selectively activate the p38 mitogen-activated protein kinase (MAPK) pathway and derepress a subset of endogenous genes repressed by DNA methylation. Selective agonists of the p38 pathway have been lacking, and our study now provides critical compounds for studying this pathway and p38 MAPK–targeted genes repressed by DNA methylation.