Sox6 Directly Silences Epsilon Globin Expression in Definitive Erythropoiesis

Abstract

Sox6 is a member of the Sox transcription factor family that is defined by the conserved high mobility group (HMG) DNA binding domain, first described in the testis determining gene, Sry. Previous studies have suggested that Sox6 plays a role in the development of the central nervous system, cartilage, and muscle. In the Sox6-deficient mouse, p100H, ɛy globin is persistently expressed, and increased numbers of nucleated red cells are present in the fetal circulation. Transfection assays in GM979 (erythroleukemic) cells define a 36–base pair region of the ɛy proximal promoter that is critical for Sox6 mediated repression. Electrophoretic mobility shift assay (EMSA) and chromatin immunoprecipitation (ChIP) assays demonstrate that Sox6 acts as a repressor by directly binding to the ɛy promoter. The normal expression of Sox6 in wild-type fetal liver and the ectopic expression of ɛy in p100H homozygous fetal liver demonstrate that Sox6 functions in definitive erythropoiesis. The present study shows that Sox6 is required for silencing of ɛy globin in definitive erythropoiesis and suggests a role for Sox6 in erythroid cell maturation. Thus, Sox6 regulation of ɛy globin might provide a novel therapeutical target in the treatment of hemoglobinopathies such as sickle cell anemia and thalassemia.

Transcriptional silencing of γ-globin by BCL11A involves long-range interactions and cooperation with SOX6

“…1A), it is likely that other factors cooperate with BCL11A to achieve their proper silencing within the b-globin locus. SOX6 has been shown previously to silence the mouse embryonic ey-globin and bh1-globin expression, probably by direct association with the ey promoter (Yi et al 2006). Given that the human g-gene behaves as an embryonic gene in the mouse erythroid trans-acting environment (Sankaran et al 2009), we hypothesized that SOX6 may also be involved in g-gene control.…”

“…A potential role for SOX6 in globin gene regulation was first recognized by analysis of the Sox6-deficient mouse. At the fetal liver stage, expression of mouse embryonic b-like globins (ey and bh1) was dramatically elevated in the Sox6-deficient p 100H mouse (Yi et al 2006). While bh1 was down-regulated rapidly in late fetal livers, the eyglobin gene was expressed persistently until birth (Yi et al 2006).…”

“…At the fetal liver stage, expression of mouse embryonic b-like globins (ey and bh1) was dramatically elevated in the Sox6-deficient p 100H mouse (Yi et al 2006). While bh1 was down-regulated rapidly in late fetal livers, the eyglobin gene was expressed persistently until birth (Yi et al 2006). SOX6 also represses ey-globin and, to a lesser extent, bh1-globin expression in definitive erythropoiesis of adult mice, as revealed by transplantation of fetal liver cells from Sox6-deficient mice into wild-type adult mice (Cohen-Barak et al 2007).…”

“…SOX6 also represses ey-globin and, to a lesser extent, bh1-globin expression in definitive erythropoiesis of adult mice, as revealed by transplantation of fetal liver cells from Sox6-deficient mice into wild-type adult mice (Cohen-Barak et al 2007). SOX6 acts as a repressor of eyglobin expression by direct binding to the ey promoter (Yi et al 2006). SOX6 has also been suggested to enhance definitive erythropoiesis in mice by stimulating erythroid cell survival, proliferation, and terminal maturation (Dumitriu et al 2006).…”

“…In addition, Sox transcription factors bind to the minor groove of DNA and cause a drastic bend of the DNA that leads to local conformational changes (Ferrari et al 1992;Connor et al 1994). Therefore, it has been suggested that SOX6 may perform part of its function as an architectural factor by organizing local chromatin structure and assembling other DNA-bound transcriptional factors into biologically active, sterically defined multiprotein transcriptional complexes (Yi et al 2006). …”