Aging Human Hematopoietic Stem Cells Manifest Profound Epigenetic Reprogramming of Enhancers That May Predispose to Leukemia

Emmalee R. Adelman, Hsuan Ting Huang, Alejandro Roisman, André Olsson, Antonio Colaprico, Tingting Qin, R. Coleman Lindsley, Rafael Bejar, Nathan Salomonis, H. Leighton Grimes, Maria E. Figueroa

Research output: Contribution to journalArticle

16 Scopus citations

Abstract

Aging is associated with functional decline of hematopoietic stem cells (HSC) as well as an increased risk of myeloid malignancies. We performed an integrative characterization of epigenomic and transcriptomic changes, including single-cell RNA sequencing, during normal human aging. Lineage-CD34+CD38- cells [HSC-enriched (HSCe)] undergo age-associated epigenetic reprogramming consisting of redistribution of DNA methylation and reductions in H3K27ac, H3K4me1, and H3K4me3. This reprogramming of aged HSCe globally targets developmental and cancer pathways that are comparably altered in acute myeloid leukemia (AML) of all ages, encompassing loss of 4,646 active enhancers, 3,091 bivalent promoters, and deregulation of several epigenetic modifiers and key hematopoietic transcription factors, such as KLF6, BCL6, and RUNX3. Notably, in vitro downregulation of KLF6 results in impaired differentiation, increased colony-forming potential, and changes in expression that recapitulate aging and leukemia signatures. Thus, age-associated epigenetic reprogramming may form a predisposing condition for the development of age-related AML. SIGNIFICANCE: AML, which is more frequent in the elderly, is characterized by epigenetic deregulation. We demonstrate that epigenetic reprogramming of human HSCs occurs with age, affecting cancer and developmental pathways. Downregulation of genes epigenetically altered with age leads to impairment in differentiation and partially recapitulates aging phenotypes.This article is highlighted in the In This Issue feature, p. 983.

Original languageEnglish (US)
Pages (from-to)1080-1101
Number of pages22
JournalCancer discovery
Volume9
Issue number8
DOIs
StatePublished - Aug 1 2019

ASJC Scopus subject areas

  • Oncology

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    Adelman, E. R., Huang, H. T., Roisman, A., Olsson, A., Colaprico, A., Qin, T., Lindsley, R. C., Bejar, R., Salomonis, N., Grimes, H. L., & Figueroa, M. E. (2019). Aging Human Hematopoietic Stem Cells Manifest Profound Epigenetic Reprogramming of Enhancers That May Predispose to Leukemia. Cancer discovery, 9(8), 1080-1101. https://doi.org/10.1158/2159-8290.CD-18-1474