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Epigenetic Heterogeneity and Mitotic Heritability Prime Endothelial Cell Gene Induction

Paul J. Turgeon, Gary C. Chan, Lucy Chen, Alisha N. Jamal, Matthew S. Yan, J. J. David Ho, Lei Yuan, Neke Ibeh, Kyung Ha Ku, Myron I. Cybulsky, William C. Aird and Philip A. Marsden
J Immunol January 29, 2020, ji1900744; DOI: https://doi.org/10.4049/jimmunol.1900744
Paul J. Turgeon
*Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario M5S 1A8, Canada;
†Keenan Research Centre, Li Ka Shing Knowledge Institute, St. Michael’s Hospital, Toronto, Ontario M5B 1T8, Canada;
‡Department of Medicine, University of Toronto, Toronto, Ontario M5S 1A8, Canada;
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Gary C. Chan
*Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario M5S 1A8, Canada;
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Lucy Chen
†Keenan Research Centre, Li Ka Shing Knowledge Institute, St. Michael’s Hospital, Toronto, Ontario M5B 1T8, Canada;
‡Department of Medicine, University of Toronto, Toronto, Ontario M5S 1A8, Canada;
§Department of Medical Biophysics, University of Toronto, Toronto, Ontario M5G 1L7, Canada;
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Alisha N. Jamal
*Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario M5S 1A8, Canada;
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Matthew S. Yan
†Keenan Research Centre, Li Ka Shing Knowledge Institute, St. Michael’s Hospital, Toronto, Ontario M5B 1T8, Canada;
‡Department of Medicine, University of Toronto, Toronto, Ontario M5S 1A8, Canada;
§Department of Medical Biophysics, University of Toronto, Toronto, Ontario M5G 1L7, Canada;
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J. J. David Ho
§Department of Medical Biophysics, University of Toronto, Toronto, Ontario M5G 1L7, Canada;
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Lei Yuan
¶Center for Vascular Biology Research at Beth Israel Deaconess Medical Center, Harvard Medical School, Harvard University, Boston, MA 02215;
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Neke Ibeh
‖Princess Margaret Cancer Center, University Health Network, Toronto, Ontario M5G 2C1, Canada;
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Kyung Ha Ku
*Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario M5S 1A8, Canada;
†Keenan Research Centre, Li Ka Shing Knowledge Institute, St. Michael’s Hospital, Toronto, Ontario M5B 1T8, Canada;
‡Department of Medicine, University of Toronto, Toronto, Ontario M5S 1A8, Canada;
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Myron I. Cybulsky
*Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario M5S 1A8, Canada;
#Department of Immunology, University of Toronto, Toronto, Ontario M5S 1A8, Canada; and
**Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario M5G 2C4, Canada
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William C. Aird
¶Center for Vascular Biology Research at Beth Israel Deaconess Medical Center, Harvard Medical School, Harvard University, Boston, MA 02215;
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Philip A. Marsden
*Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario M5S 1A8, Canada;
†Keenan Research Centre, Li Ka Shing Knowledge Institute, St. Michael’s Hospital, Toronto, Ontario M5B 1T8, Canada;
‡Department of Medicine, University of Toronto, Toronto, Ontario M5S 1A8, Canada;
§Department of Medical Biophysics, University of Toronto, Toronto, Ontario M5G 1L7, Canada;
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Key Points

  • VCAM1 is heterogeneously expressed in endothelial cells after TNF-α induction.

  • Heterogeneous VCAM1 promoter DNA methylation is mitotically heritable.

  • Heterogeneity in cytokine responsiveness occurs in many endothelial genes.

Abstract

Homogeneous populations of mature differentiated primary cell types can display variable responsiveness to extracellular stimuli, although little is known about the underlying mechanisms that govern such heterogeneity at the level of gene expression. In this article, we show that morphologically homogenous human endothelial cells exhibit heterogeneous expression of VCAM1 after TNF-α stimulation. Variability in VCAM1 expression was not due to stochasticity of intracellular signal transduction but rather to preexisting established heterogeneous states of promoter DNA methylation that were generationally conserved through mitosis. Variability in DNA methylation of the VCAM1 promoter resulted in graded RelA/p65 and RNA polymerase II binding that gave rise to a distribution of VCAM1 transcription in the population after TNF-α stimulation. Microarray analysis and single-cell RNA sequencing revealed that a number of cytokine-inducible genes shared this heterogeneous response pattern. These results show that heritable epigenetic heterogeneity is fundamental in inflammatory signaling and highlight VCAM1 as a metastable epiallele.

Footnotes

  • This work was supported by Canadian Institutes of Health Grant MOP 142307 to P.A.M.

  • The microarray data presented in this article have been submitted to the Gene Expression Omnibus (http://www.ncbi.nlm.nih.gov/geo/) under accession number GSE141374.

  • The online version of this article contains supplemental material.

  • Received September 26, 2019.
  • Accepted December 23, 2019.
  • Copyright © 2020 by The American Association of Immunologists, Inc.

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The Journal of Immunology: 206 (3)
The Journal of Immunology
Vol. 206, Issue 3
1 Feb 2021
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Epigenetic Heterogeneity and Mitotic Heritability Prime Endothelial Cell Gene Induction
Paul J. Turgeon, Gary C. Chan, Lucy Chen, Alisha N. Jamal, Matthew S. Yan, J. J. David Ho, Lei Yuan, Neke Ibeh, Kyung Ha Ku, Myron I. Cybulsky, William C. Aird, Philip A. Marsden
The Journal of Immunology January 29, 2020, ji1900744; DOI: 10.4049/jimmunol.1900744

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Epigenetic Heterogeneity and Mitotic Heritability Prime Endothelial Cell Gene Induction
Paul J. Turgeon, Gary C. Chan, Lucy Chen, Alisha N. Jamal, Matthew S. Yan, J. J. David Ho, Lei Yuan, Neke Ibeh, Kyung Ha Ku, Myron I. Cybulsky, William C. Aird, Philip A. Marsden
The Journal of Immunology January 29, 2020, ji1900744; DOI: 10.4049/jimmunol.1900744
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Print ISSN 0022-1767        Online ISSN 1550-6606