ZNF410 represses fetal globin by devoted control of CHD4/NuRD

Abstract

Major effectors of adult-stage fetal globin silencing include the transcription factors (TFs) BCL11A and ZBTB7A/LRF and the NuRD chromatin complex, although each has potential on-target liabilities for rational β-hemoglobinopathy therapeutic inhibition. Here through CRISPR screening we discover ZNF410 to be a novel fetal hemoglobin (HbF) repressing TF. ZNF410 does not bind directly to the γ-globin genes but rather its chromatin occupancy is solely concentrated at CHD4, encoding the NuRD nucleosome remodeler, itself required for HbF repression. CHD4 has two ZNF410-bound regulatory elements with 27 combined ZNF410 binding motifs constituting unparalleled genomic clusters. These elements completely account for ZNF410’s effects on γ-globin repression. Knockout of ZNF410 reduces CHD4 by 60%, enough to substantially de-repress HbF while avoiding the cellular toxicity of complete CHD4 loss. Mice with constitutive deficiency of the homolog Zfp410 are born at expected Mendelian ratios with unremarkable hematology. ZNF410 is dispensable for human hematopoietic engraftment potential and erythroid maturation unlike known HbF repressors. These studies identify a new rational target for HbF induction for the β-hemoglobin disorders with a wide therapeutic index. More broadly, ZNF410 represents a special class of gene regulator, a conserved transcription factor with singular devotion to regulation of a chromatin subcomplex.

Molecular Medicine: Found in Translation

“…54 Further support for a cofactor role for the NuRD complex in HbF repression is provided by recent findings that ZNF410, a pentadactyl DNA-binding protein, exhibits remarkable specificity for activation of the CHD4 locus, which encodes its ATP-dependent remodeling subunit. 55,56 Recent studies provide an increasingly detailed view of how g-globin gene repression is controlled (Figure 2). Whereas chromosomal looping between the LCR and each downstream globin gene is believed to be required for transcriptional activation, the choice between the expression of gand b-globin genes appears to be executed locally.…”