Disruption of the Hbs1l-Myb Locus Causes Hereditary Persistence of Fetal Hemoglobin in a Mouse Model

Abstract

The human β-globin locus is comprised of embryonic, fetal, and adult globin genes, each of which is expressed at distinct stages of pre- and postnatal development. Functional defects in globin proteins or expression results in mild to severe anemia, such as in sickle-cell disease or β-thalassemia, but the clinical symptoms of both disorders are ameliorated by persistent expression of the fetal globin genes. Recent genome-wide association studies (GWAS) identified the intergenic region between the HBS1L and MYB loci as a candidate modifier of fetal hemoglobin expression in adults. However, it remains to be clarified whether the enhancer activity within the HBS1L-MYB regulatory domain contributes to the production of fetal hemoglobin in adults. Here we report a new mouse model of hereditary persistence of fetal hemoglobin (HPFH) in which a transgene was randomly inserted into the orthologous murine Hbs1l-Myb locus. This mutant mouse exhibited typically elevated expression of embryonic globins and hematopoietic parameters similar to those observed in human HPFH. These results support the contention that mutation of the HBS1L-MYB genomic domain is responsible for elevated expression of the fetal globin genes, and this model serves as an important means for the analysis of networks that regulate fetal globin gene expression.

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SUPPLEMENTAL MATERIAL

Supplemental material for this article may be found at http://dx.doi.org/10.1128/MCB.01617-12.

ACKNOWLEDGMENTS

We thank Masanobu Morita and Ritsuko Shimizu for discussion, Hiromi Suda and Carmen Yu for technical assistance, and the Biomedical Research Core and Center for Laboratory Animal Research of Tohoku University Graduate School of Medicine for technical support.

This work was supported in part by Grants-in-Aid from the NIH (HL24415 to J.D.E.), JSPS (KAKENHI 19GS0312 to M.Y. and 22790269 to M.S.), the Tohoku University Global COE for Conquest of Signal Transduction Diseases with Network Medicine (to M.Y.), the NAITO Foundation (to M.Y.), and the Takeda Science Foundation (to M.Y.). H.Y. is a JSPS Research Fellow.