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GENE REGULATION

Targeting ZNF410 as a potential β-hemoglobinopathy therapy

Nature Genetics volume 53, pages 589–590 (2021)Cite this article

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The nucleosome remodeling and deacetylase (NuRD) complex is a chromatin modifier with a key role in the switch from fetal to adult hemoglobin. In a new study, Vinjamur et al. identify a fetal hemoglobin repressor, ZNF410, which does not directly bind the γ-globin promoter but acts through highly specific regulation of CHD4, a protein subunit of the NuRD complex, thus presenting a potential approach for therapeutic reactivation of fetal hemoglobin.

The burden of sickle cell disease (SCD) and β-thalassemia is high, affecting several millions of people globally, and is expected to increase in the years to come1. Both disorders are caused by mutations in the β-globin gene (HBB), yet, despite their apparent genetic simplicity, both display a remarkable spectrum of disease severity and share a common major genetic modifier—fetal (α2γ2) hemoglobin (HbF) levels2. The beneficial effects of HbF are lost in both disorders in the first postnatal months after completion of the hemoglobin switch. When the HbF level reaches ~1%, adult hemoglobin becomes predominant, and the diseases are manifested. Therapeutic reactivation of HbF production for these two β-hemoglobin disorders has prompted years of research focused on understanding the fetal–adult hemoglobin switch and how to derepress this switch through pharmacological and genetic or genomic approaches3. Genome-wide association studies identified BCL11A as the first key repressor protein found to silence the fetal (γ) globin genes4, which was followed by the identification of ZBTB7A (also known as LRF)5. Each of these repressors binds a cognate recognition site within the γ-globin promoter6,7. Clinical trials aimed at downregulating BCL11A through different genetic approaches (lentiviral short hairpin RNA and CRISPR–Cas-9 editing) are currently enrolling participants; this approach shows immense promise in elevating HbF and resolving disease complications8,9. However, these ‘curative’ therapies are currently available to only a fraction of the population affected by SCD and β-thalassemia, even in well-resourced countries. In the near term, a pharmacotherapeutic approach—that is, a drug that can be taken orally—is urgently needed to make therapy available worldwide10.

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Fig. 1: ZNF410 transactivation of CHD4 through 27 evolutionarily conserved DNA-binding motifs.

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Authors and Affiliations

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

    Laxminath Tumburu & Swee Lay Thein

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  1. Laxminath Tumburu
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  2. Swee Lay Thein
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Correspondence to Swee Lay Thein.

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Tumburu, L., Thein, S.L. Targeting ZNF410 as a potential β-hemoglobinopathy therapy. Nat Genet 53, 589–590 (2021). https://doi.org/10.1038/s41588-021-00817-y

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