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 language | English (US) |
|---|---|
| Pages (from-to) | 1080-1101 |
| Number of pages | 22 |
| Journal | Cancer discovery |
| Volume | 9 |
| Issue number | 8 |
| DOIs | |
| State | Published - Aug 1 2019 |
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ASJC Scopus subject areas
- Oncology
Cite this
Aging Human Hematopoietic Stem Cells Manifest Profound Epigenetic Reprogramming of Enhancers That May Predispose to Leukemia. / Adelman, Emmalee R.; Huang, Hsuan Ting; Roisman, Alejandro; Olsson, André; Colaprico, Antonio; Qin, Tingting; Lindsley, R. Coleman; Bejar, Rafael; Salomonis, Nathan; Grimes, H. Leighton; Figueroa, Maria E.
In: Cancer discovery, Vol. 9, No. 8, 01.08.2019, p. 1080-1101.Research output: Contribution to journal › Article
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TY - JOUR
T1 - Aging Human Hematopoietic Stem Cells Manifest Profound Epigenetic Reprogramming of Enhancers That May Predispose to Leukemia
AU - Adelman, Emmalee R.
AU - Huang, Hsuan Ting
AU - Roisman, Alejandro
AU - Olsson, André
AU - Colaprico, Antonio
AU - Qin, Tingting
AU - Lindsley, R. Coleman
AU - Bejar, Rafael
AU - Salomonis, Nathan
AU - Grimes, H. Leighton
AU - Figueroa, Maria E.
PY - 2019/8/1
Y1 - 2019/8/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85071059315&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85071059315&partnerID=8YFLogxK
U2 - 10.1158/2159-8290.CD-18-1474
DO - 10.1158/2159-8290.CD-18-1474
M3 - Article
C2 - 31085557
AN - SCOPUS:85071059315
VL - 9
SP - 1080
EP - 1101
JO - Cancer Discovery
JF - Cancer Discovery
SN - 2159-8274
IS - 8
ER -