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Aging Human Hematopoietic Stem Cells Manifest Profound Epigenetic Reprogramming of Enhancers That May Predispose to Leukemia.
- Source :
-
Cancer discovery [Cancer Discov] 2019 Aug; Vol. 9 (8), pp. 1080-1101. Date of Electronic Publication: 2019 May 13. - Publication Year :
- 2019
-
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 <superscript>-</superscript> CD34 <superscript>+</superscript> CD38 <superscript>-</superscript> 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 .<br /> (©2019 American Association for Cancer Research.)
- Subjects :
- Cytosine metabolism
DNA Methylation
Disease Susceptibility
Enhancer Elements, Genetic
Gene Expression Profiling
Gene Expression Regulation, Leukemic
Histones metabolism
Humans
Kruppel-Like Factor 6 genetics
Kruppel-Like Factor 6 metabolism
Leukemia pathology
Promoter Regions, Genetic
Transcription Factors metabolism
Cell Differentiation genetics
Cellular Reprogramming genetics
Cellular Senescence genetics
Epigenesis, Genetic
Hematopoietic Stem Cells metabolism
Leukemia genetics
Leukemia metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 2159-8290
- Volume :
- 9
- Issue :
- 8
- Database :
- MEDLINE
- Journal :
- Cancer discovery
- Publication Type :
- Academic Journal
- Accession number :
- 31085557
- Full Text :
- https://doi.org/10.1158/2159-8290.CD-18-1474