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PSTPIP2 connects DNA methylation to macrophage polarization in CCL4-induced mouse model of hepatic fibrosis.
Oncogene ( IF 8 ) Pub Date : 2018-Jul-11 , DOI: 10.1038/s41388-018-0383-0
Yang Yang , Xiao-qin Wu , Wan-xia Li , Hui-min Huang , Hai-di Li , Xue-yin Pan , Xiao-feng Li , Cheng Huang , Xiao-ming Meng , Lei Zhang , Xiong-wen Lv , Hua Wang , Jun Li

Macrophages play a crucial role in the progression of hepatic fibrosis (HF). In macrophages, epigenetic mechanisms are increasingly being recognized as crucial controllers of their phenotype. However, the functions of macrophage DNA methylation in experimental models of hepatic fibrosis have not been fully addressed. Here, we analyzed isolated hepatic macrophages DNA methylation from CCL4-induced (4 weeks) mice using reduced representation bisulfite sequencing (RRBS). We identified and validated the methylation status of 26 gene promoter regions associated with CpG islands. We further investigated the function of PSTPIP2 in HF by hepatic-adeno-associated virus (AAV9)-PSTPIP2 overexpression. The molecular mechanisms underlying PSTPIPS2-regulated HF were further explored in mice and RAW264.7 cell line. RRBS results show hypermethylation of PSTPIP2 (chr18: 77,843,840-77,843,968) in the 5'-UTR region. PSTPIP2 expression was significantly decreased in isolated hepatic macrophages from CCL4-induced mice. PSTPIP2 hypermethylation is mediated by the methyltransferases DNMT3a and DNMT3b in LPS-induced RAW264.7 cell line. Further investigation indicated that specific overexpression of PSTPIP2 in C57BL/6 mice reduced the inflammatory response and ameliorated liver fibrosis. These data indicated that hypermethylation of PSTPIP2 caused a mixed induction of hepatic classical macrophage (M1) and alternative macrophage (M2) biomarkers in CCL4-induced HF mice. Furthermore, overexpression of PSTPIP2 inhibited the expression of M1 markers by suppressing STAT1 activity, and enhanced the expression of M2 markers by promoting STAT6 activity. In contrast, knockdown of PSTPIP2 promoted M1 polarization and suppressed M2 polarization in vitro. Adding PSTPIP2 expression alleviates liver fibrosis and hepatic inflammation in mice by regulating macrophage polarization.

中文翻译:

PSTPIP2将DNA甲基化连接到CCL4诱导的肝纤维化小鼠模型中的巨噬细胞极化。

巨噬细胞在肝纤维化(HF)的进程中起着至关重要的作用。在巨噬细胞中,表观遗传机制越来越被认为是其表型的关键控制者。但是,在肝纤维化实验模型中巨噬细胞DNA甲基化的功能尚未完全解决。在这里,我们使用减少的代表性亚硫酸氢盐测序(RRBS)分析了来自CCL4诱导的小鼠(4周)的孤立的肝巨噬细胞DNA甲基化。我们鉴定并验证了与CpG岛相关的26个基因启动子区域的甲基化状态。我们进一步研究了肝腺相关病毒(AAV9)-PSTPIP2过表达在HF中PSTPIP2的功能。在小鼠和RAW264.7细胞系中进一步探讨了PSTPIPS2调控的HF的分子机制。RRBS结果显示在5'-UTR区域PSTPIP2的甲基化程度较高(chr18:77,843,840-77,843,968)。在来自CCL4诱导的小鼠的分离的肝巨噬细胞中,PSTPIP2表达显着降低。在LPS诱导的RAW264.7细胞系中,甲基转移酶DNMT3a和DNMT3b介导PSTPIP2的高度甲基化。进一步的研究表明,C57BL / 6小鼠中PSTPIP2的特异性过表达减少了炎症反应并改善了肝纤维化。这些数据表明PSTPIP2的甲基化过高导致在CCL4诱导的HF小鼠中肝经典巨噬细胞(M1)和替代性巨噬细胞(M2)生物标志物的混合诱导。此外,PSTPIP2的过表达通过抑制STAT1活性来抑制M1标记的表达,并通过促进STAT6活性来增强M2标记的表达。相比之下,敲低PSTPIP2促进体外M1极化和抑制M2极化。添加PSTPIP2表达可通过调节巨噬细胞极化来减轻小鼠的肝纤维化和肝炎。
更新日期:2018-07-14
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