Retinoid-Sensitive Epigenetic Regulation of the Hoxb Cluster Maintains Normal Hematopoiesis and Inhibits Leukemogenesis

Hox genes modulate the properties of hematopoietic stem cells (HSCs) and reacquired Hox expression in progenitors contributes to leukemogenesis. Here, our transcriptome and DNA methylome analyses revealed that Hoxb cluster and retinoid signaling genes are predominantly enriched in LT-HSCs, and this...

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Published in:Cell stem cell 2018-05, Vol.22 (5), p.740-754.e7
Main Authors: Qian, Pengxu, De Kumar, Bony, He, Xi C., Nolte, Christof, Gogol, Madelaine, Ahn, Youngwook, Chen, Shiyuan, Li, Zhenrui, Xu, Hanzhang, Perry, John M., Hu, Deqing, Tao, Fang, Zhao, Meng, Han, Yingli, Hall, Kate, Peak, Allison, Paulson, Ariel, Zhao, Chongbei, Venkatraman, Aparna, Box, Andrew, Perera, Anoja, Haug, Jeffrey S., Parmely, Tari, Li, Hua, Krumlauf, Robb, Li, Linheng
Format: Article
Language:English
Subjects:
acute myeloid leukemia
Animals
cis-regulatory element
CRISPR-Cas9
DNA methylation
DNMT3A mutation
Enhancer Elements, Genetic - drug effects
Enhancer Elements, Genetic - genetics
Epigenesis, Genetic - drug effects
Epigenesis, Genetic - genetics
epigenome editing
HEK293 Cells
Hematopoiesis - drug effects
Hematopoiesis - genetics
hematopoietic stem cells
Homeodomain Proteins - antagonists & inhibitors
Homeodomain Proteins - genetics
Homeodomain Proteins - metabolism
Hox genes
Hoxb cluster
Humans
Mice
Mice, Inbred C57BL
Mice, Knockout
non-canonical Wnt signaling
Retinoids - chemistry
Retinoids - pharmacology
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Summary:Hox genes modulate the properties of hematopoietic stem cells (HSCs) and reacquired Hox expression in progenitors contributes to leukemogenesis. Here, our transcriptome and DNA methylome analyses revealed that Hoxb cluster and retinoid signaling genes are predominantly enriched in LT-HSCs, and this coordinate regulation of Hoxb expression is mediated by a retinoid-dependent cis-regulatory element, distal element RARE (DERARE). Deletion of the DERARE reduced Hoxb expression, resulting in changes to many downstream signaling pathways (e.g., non-canonical Wnt signaling) and loss of HSC self-renewal and reconstitution capacity. DNA methyltransferases mediate DNA methylation on the DERARE, leading to reduced Hoxb cluster expression. Acute myeloid leukemia patients with DNMT3A mutations exhibit DERARE hypomethylation, elevated HOXB expression, and adverse outcomes. CRISPR-Cas9-mediated specific DNA methylation at DERARE attenuated HOXB expression and alleviated leukemogenesis. Collectively, these findings demonstrate pivotal roles for retinoid signaling and the DERARE in maintaining HSCs and preventing leukemogenesis by coordinate regulation of Hoxb genes. [Display omitted] •A cis-regulatory element DERARE works over long range to control Hoxb genes in HSCs•Loss of the DERARE abrogates Hoxb expression and leads to functional HSC defects•DNMT enzymes mediate DERARE methylation to repress Hoxb cluster expression•dCas9-DNMT3A targeted DNA methylation on the DERARE alleviates AML leukemogenesis Hox genes are regulators of HSC maintenance and contributors in leukemogenesis. Li and colleagues elucidate a mechanism for how the retinoid-dependent cis-regulatory element DERARE maintains normal hematopoiesis but prevents leukemogenesis by coordinate regulation of Hoxb cluster genes in a methylation-dependent manner.
ISSN:1934-5909
1875-9777
DOI:10.1016/j.stem.2018.04.012