Zinc finger protein 410 (ZNF410) (ZNF410)

Zinc finger protein 410 (ZNF410) is a transcription factor that has been identified as a critical and highly specific regulator of fetal hemoglobin (HbF) expression (UniProt Q86V48). It functions by binding to the promoter of the CHD4 gene, which encodes a core ATPase component of the Nucleosome Remodeling and Deacetylase (NuRD) complex (Vinjamur et al., Science 2021). In adult erythroid cells, the NuRD complex is responsible for the epigenetic silencing of the γ-globin genes; by maintaining CHD4 levels, ZNF410 indirectly ensures that HbF remains repressed (Ghosh et al., Nature Genetics 2021). Targeting ZNF410 mRNA or protein represents a novel therapeutic strategy for treating hemoglobinopathies such as sickle cell disease and beta-thalassemia, as its inhibition leads to a reduction in CHD4 and a subsequent robust induction of HbF. Unlike other HbF repressors like BCL11A, ZNF410 appears to have a very limited number of genomic targets, which may translate to a more favorable safety profile with fewer off-target effects. Current therapeutic approaches under investigation include the use of siRNA, antisense oligonucleotides, and CRISPR-based gene editing to knock down ZNF410 expression in hematopoietic stem cells.

Other names

APA-1Another partner for ARF 1Zinc finger protein 410

ZNF410 acts as a specific transcriptional activator of the CHD4 gene. CHD4 is a critical component of the NuRD (Nucleosome Remodeling and Deacetylase) complex, which represses the expression of fetal hemoglobin (HbF). By inhibiting ZNF410 mRNA or protein, CHD4 levels are depleted, leading to the reactivation of γ-globin genes and the production of HbF (Vinjamur et al., 2021; Ghosh et al., 2021).