Multimeric transcription factor BCL11A utilizes two zinc-finger tandem arrays to bind clustered short sequence motifs

BCL11A, a transcription factor, is vital for hematopoiesis, including B and T cell maturation and the fetal-to-adult hemoglobin switch. Mutations in BCL11A are linked to neurodevelopmental disorders. BCL11A contains two DNA-binding zinc-finger arrays, low-affinity ZF2-3 and high-affinity ZF4-6, separated by a 300-amino-acid linker. ZF2-3 and ZF4-5 share 73% identity, including five out of six DNA base-interacting residues. These arrays bind similar short sequence motifs in clusters, with the linker enabling a broader binding span. Crystallographic structures of ZF4-6, in complex with oligonucleotides from the β-globin locus region, reveal DNA sequence recognition by residues Asn756 (ZF4), Lys784 and Arg787 (ZF5). A Lys784-to-Thr mutation, linked to a neurodevelopmental disorder with persistent fetal globin expression, reduces DNA binding over 10-fold but gains interaction with a variable base pair. BCL11A isoforms may form oligomers, enhancing chromatin occupancy and repressor functions by allowing multiple copies of both low- and high-affinity ZF arrays to bind DNA. These distinctive properties, apparently conserved among vertebrates, provide essential functional flexibility to this crucial regulator.