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.