组蛋白乙酰化和甲基化修饰对MCP-1信号及肺纤维化的调控机制

Pulmonary fibrsis (PF) is a common consequence and often a central feature of many chronic lung diseases. Due to air pollution, the incidence and mortality of PF is rising year by year, which is severly threating the health of human being. Compelling evidence have demonstrated that the overexpression of MCP-1 signalling contributes to the initiation and progression of PF. With the support of our previous project of National Science Foundation of China, we found that the high gene transcriptional level is the main cause of Monocyte chemotactic protein-1(MCP-1) signal overexpression, and histone modification including histone hyperacetylation and active histone methylation marker H3K4me3 at MCP-1 promoter are involved in the enhanced transcriptional signal of MCP-1 in pulmonary fibrosis. We therefore hypothesize that aberrant histone acetylation and methylation is responsible for the overexpression of the MCP-1 signal in PF in response to profibrotic mediators, leading to the initiation and development of pulmonary fibrosis. To test this hypothesis, primary human lung fibroblasts, human lung specimens and animal model of pulmonary fibrosis will be employed to investigate the role of histone acetylation, histone methylaton and their crosstalk in the regulation of enhanced transcriptional signal of MCP-1 in PF, and to identify the key molecules that trigger and guide this process. We will further investigate the effect of blocking the MCP-1 signal mediated by histone acetylation and methylation in the process of PF by using gene knock out mice. This project will offer better understanding of the molecular mechanisms of PF underlying this epigenetic activation, and identification of key molecules in these changes may prove highly beneficial for the therapeutic strategies aiming to inhibit key genes activated by epigenetic upregulation in PF.

肺纤维化是多种慢性肺疾病的共同结局，空气污染加剧其患病率和病死率逐年上升，严重威胁人类健康。过度表达的MCP-1信号参与肺纤维化发生及进展。在前一个国家自然科学基金的资助下，我们发现肺纤维化时过度表达的MCP-1信号主要是由高转录水平造成的，与MCP-1启动子区结合的过度乙酰化组蛋白和转录激活的组蛋白甲基化标志H3K4me3参与肺纤维化时MCP-1的过度转录，我们推测组蛋白乙酰化和甲基化修饰的异常参与MCP-1的过度转录信号的调控，导致肺纤维化的发生和发展。本项目将应用原代培养的人肺成纤维细胞、肺组织标本及肺纤维化动物模型探讨组蛋白乙酰化和甲基化修饰及相互作用对肺纤维时MCP-1过度转录信号的影响，进而应用基因敲除小鼠动物模型探讨阻断组蛋白乙酰化和甲基化修饰介导的MCP-1信号对肺纤维化进程的影响。该研究有望从表观遗传调控角度完善肺纤维化的机制，为寻找新的有效的肺纤维化干预靶点奠定基础。

肺纤维化是多种慢性肺疾病的共同结局，严重威胁人类健康。研究表明，过度表达的MCP-1在肺纤维化进程中发挥重要作用，但调控其过度表达的组蛋白修饰的分子机制并不清楚。我们研究发现组蛋白乙酰化酶p300通过活化MCP-1启动子区的组蛋白H3和H4乙酰化，介导磷酸化转录因子NF-κB p65核转移及NF-κB与MCP-1启动子区结合参与促纤维因子Thrombin诱导的肺成纤维细胞中MCP-1转录表达；PKC与JNK通路参与促炎因子LPA诱导的肺成纤维细胞MCP-1的表达；组蛋白修饰酶p300,CARM1和Brg1参与博莱霉素诱导的肺纤维化时MCP-1的高表达。以上结果将为肺纤维化新的、特异性的治疗性靶点的发现奠定理论基础，也为其他组织纤维化疾病的研究提供借鉴。