Key Laboratory of Systems Biomedicine, Shanghai Center for Systems Biomedicine, Xin Hua Hospital, Shanghai Jiao Tong University, Shanghai 200240, China.
Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute and Harvard T.H. Chan School of Public Health, Boston, Massachusetts 02215, USA.
Genome Res. 2019 Feb;29(2):193-207. doi: 10.1101/gr.239053.118. Epub 2019 Jan 22.
Cell behaviors are dictated by epigenetic and transcriptional programs. Little is known about how extracellular stimuli modulate these programs to reshape gene expression and control cell behavioral responses. Here, we interrogated the epigenetic and transcriptional response of endothelial cells to VEGFA treatment and found rapid chromatin changes that mediate broad transcriptomic alterations. VEGFA-responsive genes were associated with active promoters, but changes in promoter histone marks were not tightly linked to gene expression changes. VEGFA altered transcription factor occupancy and the distal epigenetic landscape, which profoundly contributed to VEGFA-dependent changes in gene expression. Integration of gene expression, dynamic enhancer, and transcription factor occupancy changes induced by VEGFA yielded a VEGFA-regulated transcriptional regulatory network, which revealed that the small MAF transcription factors are master regulators of the VEGFA transcriptional program and angiogenesis. Collectively these results revealed that extracellular stimuli rapidly reconfigure the chromatin landscape to coordinately regulate biological responses.
细胞行为受表观遗传和转录程序的支配。目前对于细胞外刺激如何调节这些程序以重塑基因表达并控制细胞行为反应知之甚少。在这里，我们研究了内皮细胞对 VEGFA 处理的表观遗传和转录反应，发现了介导广泛转录组改变的快速染色质变化。VEGFA 反应基因与活性启动子相关联，但启动子组蛋白标记的变化与基因表达变化没有紧密联系。VEGFA 改变了转录因子占据和远端表观遗传景观，这对 VEGFA 依赖性基因表达变化有很大贡献。VEGFA 诱导的基因表达、动态增强子和转录因子占据变化的整合产生了一个 VEGFA 调节的转录调控网络，该网络揭示了小 MAF 转录因子是 VEGFA 转录程序和血管生成的主要调控因子。总的来说，这些结果表明细胞外刺激可以迅速重新配置染色质景观，以协调调节生物学反应。
