A dynamic and integrated epigenetic program at distal regions orchestrates transcriptional responses to VEGFA
- Shiyan Wang1,9,
- Jiahuan Chen1,9,
- Sara P. Garcia2,9,
- Xiaodong Liang1,9,
- Fang Zhang1,
- Pengyi Yan1,
- Huijing Yu1,
- Weiting Wei1,
- Zixuan Li1,
- Jingfang Wang1,
- Huangying Le1,
- Zeguang Han1,
- Xusheng Luo3,
- Daniel S. Day4,
- Sean M. Stevens5,
- Yan Zhang6,
- Peter J. Park4,
- Zhi-jie Liu7,
- Kun Sun1,
- Guo-cheng Yuan2,
- William T. Pu5,8 and
- Bing Zhang1
- 1Key Laboratory of Systems Biomedicine, Shanghai Center for Systems Biomedicine, Xin Hua Hospital, Shanghai Jiao Tong University, Shanghai 200240, China;
- 2Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute and Harvard T.H. Chan School of Public Health, Boston, Massachusetts 02215, USA;
- 3School of Electronic Information and Electrical Engineering, Shanghai Jiao Tong University, Shanghai 200240, China;
- 4Department for Biomedical Informatics, Harvard Medical School, Boston, Massachusetts 02115, USA;
- 5Department of Cardiology, Boston Children's Hospital, Boston, Massachusetts 02115, USA;
- 6Renji-Med Clinical Stem Cell Research Center, Renji Hospital, School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai 200127, China;
- 7Department of Molecular Medicine, University of Texas Health Science Center, San Antonio, Texas 78229, USA;
- 8Harvard Stem Cell Institute, Cambridge, Massachusetts 02138, USA
-
↵9 These authors are co-first authors and contributed equally to this work.
Abstract
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.
Footnotes
-
[Supplemental material is available for this article.]
-
Article published online before print. Article, supplemental material, and publication date are at http://www.genome.org/cgi/doi/10.1101/gr.239053.118.
-
Freely available online through the Genome Research Open Access option.
- Received May 2, 2018.
- Accepted December 12, 2018.
This article, published in Genome Research, is available under a Creative Commons License (Attribution-NonCommercial 4.0 International), as described at http://creativecommons.org/licenses/by-nc/4.0/.
