title: 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.
authors: Department of Medical Biochemistry, Tohoku University Graduate School of Medicine, Sendai, Japan.
authors: Mikiko
authors: M
authors: Suzuki
authors: Hiromi
authors: H
authors: Yamazaki
authors: Harumi Y
authors: HY
authors: Mukai
authors: Hozumi
authors: H
authors: Motohashi
authors: Lihong
authors: L
authors: Shi
authors: Osamu
authors: O
authors: Tanabe
authors: James Douglas
authors: JD
authors: Engel
authors: Masayuki
authors: M
authors: Yamamoto
mesh_terms: D000818:Animals; D002460:Cell Line; D005319:Fetal Hemoglobin / Q000235:genetics* / Q000378:metabolism*; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D020598:Proto-Oncogene Proteins c-myb / Q000235:genetics*; D034622:RNA Interference; D034741:RNA, Small Interfering; D055544:beta-Globins / Q000235:genetics*
chemical_list: D020598:Proto-Oncogene Proteins c-myb; D034741:RNA, Small Interfering; D055544:beta-Globins; D005319:Fetal Hemoglobin