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Regulation of MEIS1 by distal enhancer elements in acute leukemia.

Authors
  • Wang, Q F1
  • Li, Y J2
  • Dong, J F3
  • Li, B4
  • Kaberlein, J J3
  • Zhang, L4
  • Arimura, F E5
  • Luo, R T3
  • Ni, J6
  • He, F4
  • Wu, J4
  • Mattison, R3
  • Zhou, J4
  • Wang, C Z7
  • Prabhakar, S8
  • Nobrega, M A5
  • Thirman, M J3
  • 1 1] Department of Medicine, Section of Hematology/Oncology, University of Chicago, Chicago, IL, USA [2] CAS Key Laboratory of Genome Sciences and Information, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, China. , (China)
  • 2 1] CAS Key Laboratory of Genome Sciences and Information, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, China [2] Beijing Institute of Traditional Chinese Medicine, Beijing Hospital of Traditional Chinese Medicine Affiliated to Capital Medical University, Beijing, China. , (China)
  • 3 Department of Medicine, Section of Hematology/Oncology, University of Chicago, Chicago, IL, USA.
  • 4 CAS Key Laboratory of Genome Sciences and Information, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, China. , (China)
  • 5 Department of Human Genetics, University of Chicago, Chicago, IL, USA.
  • 6 Tongji Medical College of Huazhong, University of Science & Technology, Wuhan, China. , (China)
  • 7 Department of Anesthesia & Critical Care, University of Chicago, Chicago, IL, USA.
  • 8 Genome Institute of Singapore, Singapore. , (Singapore)
Type
Published Article
Journal
Leukemia
Publisher
Springer Nature
Publication Date
Jan 01, 2014
Volume
28
Issue
1
Pages
138–146
Identifiers
DOI: 10.1038/leu.2013.260
PMID: 24022755
Source
Medline
License
Unknown

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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