生物
表观遗传学
细胞生物学
下调和上调
基因沉默
染色质
组蛋白
基因敲除
DNA甲基化
癌症研究
纤维化
染色质免疫沉淀
组蛋白H3
基因表达调控
上皮-间质转换
转录因子
甲基化
转录调控
肺纤维化
脐静脉
染色质重塑
调节器
抄写(语言学)
内皮干细胞
基因表达
转染
表观遗传学
重编程
串扰
条件基因敲除
SMAD公司
平衡
免疫学
转分化
表观基因组
作者
Yaofeng Wang,Xing Peng,Jingjing Chen,Yun Zhang,Tinghong Zhang,Jingyuan Zhang,Jiaying Fan,Hui Zheng,Qiaoyuan Liu,Zhimin Song,Zhan‐Peng Huang,Shu Meng
标识
DOI:10.1002/advs.202515581
摘要
The lung is a highly vascularized organ in which endothelial cells (ECs) play a pivotal role in maintaining tissue homeostasis and regulating gas-blood exchange. Increasing evidence suggests that endothelial-to-mesenchymal transition (EndoMT) contributes to fibrosis; however, the underlying epigenetic mechanisms remain incompletely understood. Here, we identify disruptor of telomeric silencing 1-like (DOT1L), a histone H3 lysine 79 (H3K79) methyltransferase, as a key epigenetic regulator of EndoMT and fibrotic progression. In human umbilical vein ECs, TGFβ stimulation upregulated DOT1L expression and increased H3K79me2 levels during EndoMT. DOT1L knockdown abrogated H3K79 methylation and suppressed the expression of fibrosis-associated genes. Chromatin immunoprecipitation analysis revealed that direct binding of SMAD2 to the DOT1L promoter increased its transcription and promoted H3K79me2 deposition at fibrosis-related gene loci following TGFβ2 stimulation. In vivo, endothelial lineage-tracing in mice demonstrated H3K79me2 accumulation in ECs undergoing EndoMT during bleomycin-induced pulmonary fibrosis. Importantly, endothelial-specific deletion of Dot1L significantly attenuated fibrotic remodeling, collagen deposition, and mesenchymal marker expression. Collectively, these findings establish DOT1L as a critical epigenetic driver of EndoMT and pulmonary fibrosis through H3K79me2-mediated transcriptional activation, highlighting it as a potential therapeutic target in fibrotic lung disease.
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