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

Publication date: 3 May 2018
Source:Cell Stem Cell, Volume 22, Issue 5
Author(s): Pengxu Qian, Bony De Kumar, Xi C. He, Christof Nolte, Madelaine Gogol, Youngwook Ahn, Shiyuan Chen, Zhenrui Li, Hanzhang Xu, John M. Perry, Deqing Hu, Fang Tao, Meng Zhao, Yingli Han, Kate Hall, Allison Peak, Ariel Paulson, Chongbei Zhao, Aparna Venkatraman, Andrew Box, Anoja Perera, Jeffrey S. Haug, Tari Parmely, Hua Li, Robb Krumlauf, Linheng Li
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.

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Teaser

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.


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