Krüppel-Like Factors Orchestrate Endothelial Gene Expression Through Redundant and Non-Redundant Enhancer Networks.
Krüppel-Like Factors Orchestrate Endothelial Gene Expression Through Redundant and Non-Redundant Enhancer Networks.
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DOI：
10.1161/jaha.121.024303
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发表时间：
2023-02-21
影响因子：
5.4
通讯作者：
Jain, Mukesh K.
中科院分区：
文献类型：
--
作者：
Sweet, David R.;Padmanabhan, Roshan;Liao, Xudong;Dashora, Himanshu R.;Tang, Xinmiao;Nayak, Lalitha;Jain, Rajan;De Val, Sarah;Vinayachandran, Vinesh;Jain, Mukesh K.
内皮细胞的正常功能对血管的完整性和机体的存活至关重要。过去20年的研究已经确定了KLF （kr<s:1>样pel因子）蛋白家族的两个成员，KLF2和KLF4，作为内皮功能的节点调节因子。引人注目的是，KLF2和KLF4的诱导性出生后缺失导致广泛的血管泄漏、凝血功能障碍和快速死亡。重要的是，虽然转录组学研究揭示了基因表达的深刻变化，但这些变化背后的分子机制仍然知之甚少。在这里，我们试图确定KLF2和KLF4在多个血管床中的转录控制机制，以进一步了解它们作为关键内皮调节因子的作用。我们整合了多个转基因小鼠模型的染色质占用和转录研究，证明KLF2和KLF4在心肺内皮中具有重叠但不同的结合模式和转录靶点。在机制上，KLFs在启动子和增强子中使用开放的染色质区域，并以控制微血管转录的特定环境模式结合。重要的是，这发生在体内的稳态中，没有额外的外源刺激。总之，这项工作提供了血管种群中转录和功能异质性背后的机制，同时也为探索体内微血管内皮动力学建立了工具。
Proper function of endothelial cells is critical for vascular integrity and organismal survival. Studies over the past 2 decades have identified 2 members of the KLF (Krüppel‐like factor) family of proteins, KLF2 and KLF4, as nodal regulators of endothelial function. Strikingly, inducible postnatal deletion of both KLF2 and KLF4 resulted in widespread vascular leak, coagulopathy, and rapid death. Importantly, while transcriptomic studies revealed profound alterations in gene expression, the molecular mechanisms underlying these changes remain poorly understood. Here, we seek to determine mechanisms of KLF2 and KLF4 transcriptional control in multiple vascular beds to further understand their roles as critical endothelial regulators. We integrate chromatin occupancy and transcription studies from multiple transgenic mouse models to demonstrate that KLF2 and KLF4 have overlapping yet distinct binding patterns and transcriptional targets in heart and lung endothelium. Mechanistically, KLFs use open chromatin regions in promoters and enhancers and bind in context‐specific patterns that govern transcription in microvasculature. Importantly, this occurs during homeostasis in vivo without additional exogenous stimuli. Together, this work provides mechanistic insight behind the well‐described transcriptional and functional heterogeneity seen in vascular populations, while also establishing tools into exploring microvascular endothelial dynamics in vivo.
影响因子：
1.7
作者：
Chavkin NW;Walsh K;Hirschi KK
通讯作者：
Hirschi KK