Regulation of MEIS1 by distal enhancer elements in acute leukemia View Full Text


Ontology type: schema:ScholarlyArticle     


Article Info

DATE

2014-01

AUTHORS

Qian-fei Wang, Ya-jun Li, Jing-fang Dong, Bo Li, Joseph J. Kaberlein, Lin Zhang, Fábio Eiji Arimura, Roger T. Luo, Jun Ni, Fuhong He, Jun Wu, Ryan Mattison, Jing Zhou, Chong-zhi Wang, Shyam Prabhakar, Marcelo A. Nobrega, Michael J. Thirman

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. More... »

PAGES

138

Identifiers

URI

http://scigraph.springernature.com/pub.10.1038/leu.2013.260

DOI

http://dx.doi.org/10.1038/leu.2013.260

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1004374600

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/24022755


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