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Molecular and Cellular Biology, July 2008, p. 4609-4619, Vol. 28, No. 14
0270-7306/08/$08.00+0     doi:10.1128/MCB.01652-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

MicroRNA-126 Regulates HOXA9 by Binding to the Homeobox{triangledown}

Wei-Fang Shen,1* Yu-Long Hu,1 Lalita Uttarwar,1 Emmanuelle Passegue,2 and Corey Largman1*

Department of Medicine, Department of Veterans Affairs and University of California, San Francisco, California,1 Program of Development and Stem Cell Biology, Department of Medicine, University of California, San Francisco, California2

Received 6 September 2007/ Returned for modification 17 October 2007/ Accepted 30 April 2008

The PicTar program predicted that microRNA-126 (miR-126), miR-145, and let-7s target highly conserved sites within the Hoxa9 homeobox. There are increased nucleotide constraints in the three microRNA seed sites among Hoxa9 genes beyond that required to maintain protein identity, suggesting additional functional conservation. In preliminary experiments, forced expression of these microRNAs in Hoxa9-immortalized bone marrow cells downregulated the HOXA9 protein and caused loss of biological activity. The microRNAs were shown to target their predicted sites within the homeobox. miR-126 and Hoxa9 mRNA are coexpressed in hematopoietic stem cells and downregulated in parallel during progenitor cell differentiation; however, miR-145 is barely detectable in hematopoietic cells, and let-7s are highly expressed in bone marrow progenitors, suggesting that miR-126 may function in normal hematopoietic cells to modulate HOXA9 protein. In support of this hypothesis, expression of miR-126 alone in MLL-ENL-immortalized bone marrow cells decreased endogenous HOXA9 protein, while inhibition of endogenous miR-126 increased expression of HOXA9 in F9 cells.

* Corresponding author. Mailing address: 151H, VA Medical Center, 4150 Clement Street, San Francisco, CA 94121. Phone: (415) 750-2254. Fax: (415) 750-6959. E-mail for Corey Largman: largman{at}cgl.ucsf.edu. E-mail for Wei-Fang Shen: wfshen{at}itsa.ucsf.edu

{triangledown} Published ahead of print on 12 May 2008.

Molecular and Cellular Biology, July 2008, p. 4609-4619, Vol. 28, No. 14
0270-7306/08/$08.00+0     doi:10.1128/MCB.01652-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.





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