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

Author

Listed:
  • John R. Horton

    (University of Texas MD Anderson Cancer Center)

  • Meigen Yu

    (University of Texas MD Anderson Cancer Center)

  • Jujun Zhou

    (University of Texas MD Anderson Cancer Center)

  • Melody Tran

    (University of Texas MD Anderson Cancer Center)

  • Rithvi R. Anakal

    (University of Texas MD Anderson Cancer Center)

  • Yue Lu

    (University of Texas MD Anderson Cancer Center)

  • Robert M. Blumenthal

    (The University of Toledo College of Medicine and Life Sciences)

  • Xiaotian Zhang

    (McGovern Medical School)

  • Yun Huang

    (Texas A&M University)

  • Xing Zhang

    (University of Texas MD Anderson Cancer Center)

  • Xiaodong Cheng

    (University of Texas MD Anderson Cancer Center)

Abstract

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.

Suggested Citation

  • John R. Horton & Meigen Yu & Jujun Zhou & Melody Tran & Rithvi R. Anakal & Yue Lu & Robert M. Blumenthal & Xiaotian Zhang & Yun Huang & Xing Zhang & Xiaodong Cheng, 2025. "Multimeric transcription factor BCL11A utilizes two zinc-finger tandem arrays to bind clustered short sequence motifs," Nature Communications, Nature, vol. 16(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-58998-7
    DOI: 10.1038/s41467-025-58998-7
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