Summary

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.

Overall design

We profiled the human HSCe (Lineage-, CD34+, CD38-) transcriptome with aging at the single cell level. Single-cell RNAseq was performed on FACS isolated human bone marrow derived HSCe from 5 young (24-37 yo) and 4 aged donor (64-71 yo). Donors had no known hematological malignancy.

Contributors

Emmalee R Adelman 1 2 3, Hsuan-Ting Huang # 1 2, Alejandro Roisman # 1 2, André Olsson 4, Antonio Colaprico 1 2, Tingting Qin 5, R Coleman Lindsley 6, Rafael Bejar 7, Nathan Salomonis 8, H Leighton Grimes 4, Maria E Figueroa 9 2

Contact

mef162@miami.edu.(Maria E Figueroa)