Trans-acting factors involved in the transcriptional switch from fetal to adult hemoglobin production
| Factor . | Description . | Biologic role . | Mechanism of action/comment . | Method of identification as regulator of γ-globin expression . | References . |
|---|---|---|---|---|---|
| HBS1L-MYB | HBS1L: GTP-binding protein MYB: proto-oncogene | Unclear | Altered MYB expression influences γ-globin gene expression | Linkage analysis and GWAS | 71,72 |
| BCL11A | Zinc-finger transcription factor | Repressor of γ-globin gene expression | Binds to HS3 and γδ intergenic region; interacts with SOX6 | Linkage analysis and GWAS; β-YAC/BCL11A–deficient mice; shRNA knockdown in human erythroid cells | 5, 6, 49, 74, 75, 76 |
| SOX6 | SRY family of HMG box transcription factors | Involved in silencing of mouse embryonic globin genes; interacts with BCL11A to repress γ-globin gene expression | Directly interacts with BCL11A; binds to proximal γ-globin gene promoters to recruit BCL11A | Chromatin immunoprecipitation studies of murine ϵY-globin promoter; coimmunoprecipitates with BCL11A | 75, 77 |
| KLF1 (EKLF) | Erythroid-specific Kruppel-like factor | Repressor of γ-globin gene expression | Haploinsufficiency results in HPFH; directly interacts with CBP/p300 and BRG1 and recruits Sin3A and HDAC1 | Linkage analysis and GWAS; β-YAC/KLF1–deficient mice; shRNA knockdown in human erythoid cells | 7, 81 |
| p22NF-E4 | Fetal erythroid-specific transcription factor | Activator of γ-globin gene expression; interacts with CP2 to form SSP | Transcriptional activation of γ-globin gene expression | Biochemical found as component of SSP bound to γ-globin promoter; ectopic expression increased γ-globin expression in cord blood cells and delays fetal to adult Hb switch in β-YAC mice | 94, 96, 97 |
| COUP-TFII | Orphan nuclear transcription factor | Binds to DR-like sequences in proximal γ-globin gene promoters | Repressor of γ-globin gene expression | Binds DR-like sequence in γ-globin promoters; increased γ-globin expression observed when repressed by high levels of stem cell factor or shRNA knockdown in human erythroid cells | 90, 91 |
| DRED (TR2/TR4) | Orphan nuclear transcription factor | Binds to DR1 sequences in proximal γ-globin gene promoters | Repressor of γ-globin gene expression | Identified as repressor of murine embryonic globin genes; binds γ-globin promoters | 8, 85 |
| FOP | Chromatin-associated protein that directly interacts with and is methylated by PRMT1 | Regulator or repressor of γ-globin gene expression | shRNA-mediated knockdown of FOP reduces levels of Sox6 but does not alter levels of BCL11A in developing adult erythroid cells | Levels of FOP are reduced in erythroblasts derived from fetal liver compared with adult blood cells; increased γ-globin expression after shRNA knockdown in fetal liver cells of β-YAC mice and erythroid cells derived from normal and β-thalassemic donors | 95 |
| Factor . | Description . | Biologic role . | Mechanism of action/comment . | Method of identification as regulator of γ-globin expression . | References . |
|---|---|---|---|---|---|
| HBS1L-MYB | HBS1L: GTP-binding protein MYB: proto-oncogene | Unclear | Altered MYB expression influences γ-globin gene expression | Linkage analysis and GWAS | 71,72 |
| BCL11A | Zinc-finger transcription factor | Repressor of γ-globin gene expression | Binds to HS3 and γδ intergenic region; interacts with SOX6 | Linkage analysis and GWAS; β-YAC/BCL11A–deficient mice; shRNA knockdown in human erythroid cells | 5, 6, 49, 74, 75, 76 |
| SOX6 | SRY family of HMG box transcription factors | Involved in silencing of mouse embryonic globin genes; interacts with BCL11A to repress γ-globin gene expression | Directly interacts with BCL11A; binds to proximal γ-globin gene promoters to recruit BCL11A | Chromatin immunoprecipitation studies of murine ϵY-globin promoter; coimmunoprecipitates with BCL11A | 75, 77 |
| KLF1 (EKLF) | Erythroid-specific Kruppel-like factor | Repressor of γ-globin gene expression | Haploinsufficiency results in HPFH; directly interacts with CBP/p300 and BRG1 and recruits Sin3A and HDAC1 | Linkage analysis and GWAS; β-YAC/KLF1–deficient mice; shRNA knockdown in human erythoid cells | 7, 81 |
| p22NF-E4 | Fetal erythroid-specific transcription factor | Activator of γ-globin gene expression; interacts with CP2 to form SSP | Transcriptional activation of γ-globin gene expression | Biochemical found as component of SSP bound to γ-globin promoter; ectopic expression increased γ-globin expression in cord blood cells and delays fetal to adult Hb switch in β-YAC mice | 94, 96, 97 |
| COUP-TFII | Orphan nuclear transcription factor | Binds to DR-like sequences in proximal γ-globin gene promoters | Repressor of γ-globin gene expression | Binds DR-like sequence in γ-globin promoters; increased γ-globin expression observed when repressed by high levels of stem cell factor or shRNA knockdown in human erythroid cells | 90, 91 |
| DRED (TR2/TR4) | Orphan nuclear transcription factor | Binds to DR1 sequences in proximal γ-globin gene promoters | Repressor of γ-globin gene expression | Identified as repressor of murine embryonic globin genes; binds γ-globin promoters | 8, 85 |
| FOP | Chromatin-associated protein that directly interacts with and is methylated by PRMT1 | Regulator or repressor of γ-globin gene expression | shRNA-mediated knockdown of FOP reduces levels of Sox6 but does not alter levels of BCL11A in developing adult erythroid cells | Levels of FOP are reduced in erythroblasts derived from fetal liver compared with adult blood cells; increased γ-globin expression after shRNA knockdown in fetal liver cells of β-YAC mice and erythroid cells derived from normal and β-thalassemic donors | 95 |
GWAS indicates genome-wide association study; and SSP, stage selector protein.