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Transcriptional Control and Signal Transduction

Regulation of MEIS1 by distal enhancer elements in acute leukemia

Leukemia volume 28, pages 138–146 (2014)Cite this article

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Abstract

Aberrant activation of the three-amino-acid-loop extension homeobox gene MEIS1 shortens the latency and accelerates the onset and progression of acute leukemia, yet the molecular mechanism underlying persistent activation of the MEIS1 gene in leukemia remains poorly understood. Here we used a combined comparative genomics analysis and an in vivo transgenic zebrafish assay to identify six regulatory DNA elements that are able to direct green fluorescent protein expression in a spatiotemporal manner during zebrafish embryonic hematopoiesis. Analysis of chromatin characteristics and regulatory signatures suggests that many of these predicted elements are potential enhancers in mammalian hematopoiesis. Strikingly, one of the enhancer elements (E9) is a frequent integration site in retroviral-induced mouse acute leukemia. The genomic region corresponding to enhancer E9 is differentially marked by H3K4 monomethylation and H3K27 acetylation, hallmarks of active enhancers, in multiple leukemia cell lines. Decreased enrichment of these histone marks is associated with downregulation of MEIS1 expression during hematopoietic differentiation. Further, MEIS1/HOXA9 transactivate this enhancer via a conserved binding motif in vitro, and participate in an autoregulatory loop that modulates MEIS1 expression in vivo. Our results suggest that an intronic enhancer regulates the expression of MEIS1 in hematopoiesis and contributes to its aberrant expression in acute leukemia.

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Acknowledgements

We thank Dr Robert K Slany (University Erlangen) for providing the MLL-ENL-inducible cell line and Dr Andrew S McCallion for providing the pXIG_cfos_GW plasmid. We thank Qianben Wang (Ohio State University) for his help with the ChIP assay and advice on the experimental design. This research was supported by the National Institutes of Health Grant CA105049 (MJT), a Leukemia & Lymphoma Society Translational Research Program grant (MJT), the family of Jerome Thrall, the National Natural Science Foundation of China (Grant number 81070442 (Q-fW)) and by the Young Investigator Award from the Cancer Research Foundation (Q-fW). This work was also supported in part by the National Natural Science Foundation of China (Grant number 81100380 (Y-jL)), 100 Talents Program of Chinese Academy of Sciences (to Q-fW) and the Knowledge Innovation Program of the Chinese Academy of Sciences (to Y-jL).

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Authors and Affiliations

  1. Department of Medicine, Section of Hematology/Oncology, University of Chicago, Chicago, IL, USA

    Q-f Wang, J-f Dong, J J Kaberlein, R T Luo, R Mattison & M J Thirman

  2. CAS Key Laboratory of Genome Sciences and Information, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, China

    Q-f Wang, Y-j Li, B Li, L Zhang, F He, J Wu & J Zhou

  3. Beijing Institute of Traditional Chinese Medicine, Beijing Hospital of Traditional Chinese Medicine Affiliated to Capital Medical University, Beijing, China

    Y-j Li

  4. Department of Human Genetics, University of Chicago, Chicago, IL, USA

    F E Arimura & M A Nobrega

  5. Tongji Medical College of Huazhong, University of Science & Technology, Wuhan, China

    J Ni

  6. Department of Anesthesia & Critical Care, University of Chicago, Chicago, IL, USA

    C-z Wang

  7. Genome Institute of Singapore, Singapore

    S Prabhakar

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  1. Q-f Wang
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Correspondence to Q-f Wang or M J Thirman.

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Author contributions

Q-fW designed research, performed the experiments, contributed to data analysis and wrote the paper; MJT supervised the project, design the research and wrote the paper; Y-jL performed the experiments, analyzed the data, prepared the figures and wrote the paper; BL, LZh, J-fD, JZh, performed experiments; FEA and MAN performed the zebrafish assay; SP, F-hH and JW performed genomic analysis; and JN, RM, JK, RTL and CW performed PCR assay, construct cloning and mutagenesis.

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Wang, Qf., Li, Yj., Dong, Jf. et al. Regulation of MEIS1 by distal enhancer elements in acute leukemia. Leukemia 28, 138–146 (2014). https://doi.org/10.1038/leu.2013.260

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