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Transcription factor competition at the γ-globin promoters controls hemoglobin switching. Liu N, Xu S, Yao Q, et al., Nat Genet 2021; 53(4):511-520 The switch between fetal and adult hemoglobin is mediated by a transcriptional repressor (BCL11A) and an activator (NF-Y) competing for binding within a discrete region of the γ-globin promoter regions. In the early postnatal period, hemoglobin switches from fetal to adult forms. Suppression of fetal γ-globin is mediated in part by binding of BCL11A, a γ-globin repressor, to a distal motif. Liu et al. further elaborate upon the mechanisms underlying repression of fetal hemoglobin. CRISPR Cas-9 was performed across the β-globin cluster gene in order to identify regulatory elements within coding and noncoding regions. Targeting dCas9-VP64 (an activator) or dCas9-KRAB (a repressor) to the body or flank of the γ-globin gene increased and decreased HbF expression respectively, as expected. An unexpected finding emerged in a screen using inactive Cas9 (dCas), which binds DNA without introducing breaks: when targeted to the BCL11A binding motif ( 115 bp), dCas paradoxically reduced HbF expression, raising the possibility of an unidentified activator being prevented from binding to that site. The authors hypothesized that dCas9 protein binding to the BCL11A site sterically hindered NF-Y binding or displaced binding at the NF-Y site. Indeed, NF-Y knockdown reduced γ-globin expression and inhibited a looping interaction between the γ-globin gene and the upstream locus control region. Chromatin occupancy peaks reflecting transcription factor binding were reduced by NF-Y knockdown. In CD34+ cells undergoing erythroid differentiation, knocking out BCL11A acutely decreased BCL11A expression, increased NF-Y and TATA box-binding protein (TBP) binding at γ-globin promoters, and caused a small but significant increase in chromatin accessibility, with no changes in γ-globin protein. After 72 h, the BCL11A knockout showed increased NF-Y occupancy at γ-globin promoters and increased chromatin accessibility. This indicates that NF-Y binds to γ-globin promotors soon after BCL11A depletion, increasing chromatin accessibility and transcriptional activation. Based on these findings, the authors propose a model for the initiation of hemoglobin switching whereby BCL11A binds at a distal sequence, creating a steric barrier that prevents NF-Y from binding at a proximal promoter motif. In cells with low BCL11A expression, NF-Y occupies the γ-globin promoter unhindered and modifies chromatin to encourage γ-globin expression.