European Center for Angioscience (ECAS), Medical Faculty Mannheim, Heidelberg University, Heidelberg, Germany.
Division of Vascular Oncology and Metastasis, German Cancer Research Center (DKFZ-ZMBH Alliance), Heidelberg, Germany.
Elife. 2018 May 11;7:e34423. doi: 10.7554/eLife.34423.
Maintenance of a quiescent and organotypically-differentiated layer of blood vessel-lining endothelial cells (EC) is vital for human health. Yet, the molecular mechanisms of vascular quiescence remain largely elusive. Here we identify the genome-wide transcriptomic program controlling the acquisition of quiescence by comparing lung EC of infant and adult mice, revealing a prominent regulation of TGFß family members. These transcriptomic changes are distinctly accompanied by epigenetic modifications, measured at single CpG resolution. Gain of DNA methylation affects developmental pathways, including NOTCH signaling. Conversely, loss of DNA methylation preferentially occurs in intragenic clusters affecting intronic enhancer regions of genes involved in TGFβ family signaling. Functional experiments prototypically validated the strongly epigenetically regulated inhibitors of TGFβ family signaling SMAD6 and SMAD7 as regulators of EC quiescence. These data establish the transcriptional and epigenetic landscape of vascular quiescence that will serve as a foundation for further mechanistic studies of vascular homeostasis and disease-associated activation.
维持静止且具有器官特异性分化的血管内皮细胞（EC）层对于人类健康至关重要。然而，血管静止的分子机制在很大程度上仍难以捉摸。在这里，我们通过比较婴儿和成年小鼠的肺 EC，确定了控制其获得静止状态的全基因组转录组程序，揭示了 TGFβ 家族成员的重要调控作用。这些转录组变化伴随着明显的表观遗传修饰，在单个 CpG 分辨率下进行测量。DNA 甲基化的获得会影响发育途径，包括 NOTCH 信号通路。相反，DNA 甲基化的丧失则更倾向于发生在影响 TGFβ 家族信号转导相关基因内含子增强子区域的基因内簇中。功能实验初步验证了 TGFβ 家族信号转导的强烈受表观遗传调控的抑制剂 SMAD6 和 SMAD7 是 EC 静止的调节因子。这些数据建立了血管静止的转录组和表观遗传景观，将为进一步研究血管稳态和与疾病相关的激活的机制提供基础。
