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GENE REGULATION

Switching from fetal to adult hemoglobin

Nature Genetics volume 50, pages 478–480 (2018)Cite this article

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The switch from fetal to adult hemoglobin relies on repression or silencing of the upstream γ-globin gene, but identification of the transcriptional repressors that bind to the sites at which a cluster of naturally occurring variants associated with HPFH (hereditary persistence of fetal hemoglobin) are found has been elusive. A new study provides mechanistic evidence for the direct binding of BCL11A and ZBTB7A, two previously identified γ-globin gene repressors.

In healthy humans, a shift from γ-globin to β-globin gene expression around birth underlies the switch from fetal (α2γ2; HbF) to adult (α2β2; HbA) hemoglobin production, such that by 6 months of age the major hemoglobin is HbA. The hemoglobin switch, however, is not total or irreversible; all adults retain the ability to produce residual levels of HbF (<1% of total hemoglobin)1. The degree of HbF persistence varies between adults and is largely genetically controlled. Inappropriately high γ-globin gene expression in adults is associated with HPFH, caused by HBB cluster deletions or point mutations in the proximal promoter of HBG1 and HBG2 (γ-globin genes)2. While persistence of high levels of HbF has no clinical consequences in healthy individuals, coinheritance of HPFH with either of the two major β-hemoglobin disorders—sickle cell disease (SCD) or β-thalassemia—alleviates their clinical severity. The point mutations associated with HPFH are characterized as resulting in significant elevation of HbF, which ranges from 10–40% of total hemoglobin in heterozygotes. These mutations are clustered in two regions, located 115 and 200 bp upstream of the transcription start site. They were long postulated to be potential binding sites for γ-globin gene repressors, but identification of the transcription factors binding to these sites has been elusive3. BCL11A and ZBTB7A (also known as LRF) are two recently identified γ-globin gene repressors. It has not been possible to demonstrate direct binding of BCL11A to γ-globin gene promoters, leading to the hypothesis that BCL11A activates the γ-globin genes indirectly via long-range interactions in the HBB complex4,5. In this issue, Martyn and colleagues6 demonstrate for the first time that BCL11A and ZBTB7A are able to directly bind to the promoter of the γ-globin gene.

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Fig. 1: Point mutations in γ-globin gene promoters disrupt binding of transcriptional repressors, resulting in elevated fetal hemoglobin levels in adulthood.

References

  1. Stamatoyannopoulos, G. Exp. Hematol. 33, 259–271 (2005).

    Article  CAS  Google Scholar 

  2. Thein, S. L., Menzel, S., Lathrop, M. & Garner, C. Hum. Mol. Genet. 18, R216–R223 (2009).

    Article  CAS  Google Scholar 

  3. Giardine, B. et al. Nat. Genet. 43, 295–301 (2011).

    Article  CAS  Google Scholar 

  4. Xu, J. et al. Genes Dev. 24, 783–798 (2010).

    Article  CAS  Google Scholar 

  5. Jawaid, K., Wahlberg, K., Thein, S. L. & Best, S. Blood Cells Mol. Dis. 45, 140–146 (2010).

    Article  CAS  Google Scholar 

  6. Martyn, G. E. et al. Nat. Genet. http://dx.doi.org/10.1038/s41588-018-0085-0 (2018).

  7. Menzel, S. et al. Nat. Genet. 39, 1197–1199 (2007).

    Article  CAS  Google Scholar 

  8. Uda, M. et al. Proc. Natl Acad. Sci. USA 105, 1620–1625 (2008).

    Article  CAS  Google Scholar 

  9. Bauer, D. E. et al. Science 342, 253–257 (2013).

    Article  CAS  Google Scholar 

  10. Xu, J. et al. Science 334, 993–996 (2011).

    Article  CAS  Google Scholar 

  11. Canver, M. C. et al. Nature 527, 192–197 (2015).

    Article  CAS  Google Scholar 

  12. Maeda, T. et al. Nature 433, 278–285 (2005).

    Article  CAS  Google Scholar 

  13. Masuda, T. et al. Science 351, 285–289 (2016).

    Article  CAS  Google Scholar 

  14. Hoban, M. D., Orkin, S. H. & Bauer, D. E. Blood 127, 839–848 (2016).

    Article  CAS  Google Scholar 

  15. Traxler, E. A. et al. Nat. Med. 22, 987–990 (2016).

    Article  CAS  Google Scholar 

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  1. National Heart, Lung and Blood Institute/NIH, Sickle Cell Branch, Bethesda, MD, USA

    Xunde Wang & Swee Lay Thein

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  1. Xunde Wang
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Correspondence to Swee Lay Thein.

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Wang, X., Thein, S. Switching from fetal to adult hemoglobin. Nat Genet 50, 478–480 (2018). https://doi.org/10.1038/s41588-018-0094-z

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