肺纤维化
JAG1
特发性肺纤维化
癌症研究
纤维化
表观遗传学
发病机制
生物
基因沉默
肌成纤维细胞
下调和上调
基因敲除
Notch信号通路
肺
信号转导
免疫学
医学
病理
细胞生物学
内科学
细胞凋亡
基因
生物化学
作者
Di Yang,Peng Xu,Haibi Su,Wen Zhong,Jie Xu,Zhenghua Su,Xinhua Liu
标识
DOI:10.1038/s41419-021-04365-5
摘要
Idiopathic pulmonary fibrosis (IPF) is a progressive interstitial lung disease with increasing occurrence, high death rates, and unfavorable treatment regimens. The pathogenesis underlying IPF is complex and the epigenetic contributions to IPF are largely unknown. Recent studies have shown that DOT1L (Disruptor of telomeric silencing-1 like), a histone H3K79 methyltransferase, contributes to fibrosis response, but its role in IPF remains unclear. DOT1L, H3K79me3, and the profibrotic proteins levels were upregulated in the pulmonary fibrosis models both in vivo and in vitro. Lentivirus-mediated DOT1L knockdown or DOT1L-specific inhibitor EPZ5676 alleviated the pathogenesis of bleomycin-induced mouse pulmonary fibrosis. Furthermore, heterozygous DOT1L-deficient mice (Dot1l+/-) showed less sensitive to pulmonary fibrosis, as shown by decreased lung fibrosis phenotypes in vivo. Mechanically, DOT1L regulated TGF-β1-induced fibroblasts fibrosis by increasing enrichments of H3K79me3 on the promoter of Jag1 gene (encoding the Notch ligand Jagged1), enhancing the expression of Jagged1, which in turn stimulated exuberant Notch signaling and actuated the fibrosis response. In conclusion, our study confirmed DOT1L to be an epigenetic modifier in the pathogenesis of lung fibrosis, revealed a counterbalancing mechanism governing Jag1 transcription by modulating H3K79 trimethylation at the Jag1 promoter, activating the Notch signaling, and affecting the expression of profibrotic proteins to accelerate the lung fibrosis.
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