Tracing human stem cell lineage during development using DNA methylation

Lucas A. Salas; John K. Wiencke; Devin C. Koestler; Ze Zhang; Brock C. Christensen; Karl T. Kelsey

doi:10.1101/gr.233213.117

Tracing human stem cell lineage during development using DNA methylation

¹Department of Epidemiology, Geisel School of Medicine, Dartmouth College, Lebanon, New Hampshire 03756, USA;
²Department of Neurological Surgery, Institute for Human Genetics, University of California San Francisco, San Francisco, California 94158, USA;
³Department of Biostatistics, University of Kansas Medical Center, Kansas City, Kansas 66160, USA;
⁴Department of Epidemiology, Brown University, Providence, Rhode Island 02912, USA;
⁵Department of Pathology and Laboratory Medicine, Brown University, Providence, Rhode Island 02912, USA;
⁶Department of Molecular and Systems Biology, Geisel School of Medicine, Dartmouth College, Lebanon, New Hampshire 03756, USA;
⁷Department of Community and Family Medicine, Geisel School of Medicine, Dartmouth College, Lebanon, New Hampshire 03756, USA

↵8 These authors contributed equally to this work.
↵9 These authors contributed equally to this work.

Corresponding author: john.wiencke{at}ucsf.edu

Abstract

Stem cell maturation is a fundamental, yet poorly understood aspect of human development. We devised a DNA methylation signature deeply reminiscent of embryonic stem cells (a fetal cell origin signature, FCO) to interrogate the evolving character of multiple human tissues. The cell fraction displaying this FCO signature was highly dependent upon developmental stage (fetal versus adult), and in leukocytes, it described a dynamic transition during the first 5 yr of life. Significant individual variation in the FCO signature of leukocytes was evident at birth, in childhood, and throughout adult life. The genes characterizing the signature included transcription factors and proteins intimately involved in embryonic development. We defined and applied a DNA methylation signature common among human fetal hematopoietic progenitor cells and have shown that this signature traces the lineage of cells and informs the study of stem cell heterogeneity in humans under homeostatic conditions.

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.233213.117.
Freely available online through the Genome Research Open Access option.

Received December 1, 2017.
Accepted July 27, 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/.