Direct Promoter Repression by BCL11A Controls the Fetal to Adult Hemoglobin Switch

Nan Liu, Victoria V. Hargreaves, Qian Zhu, Jesse V. Kurland, Jiyoung Hong, Woojin Kim, Falak Sher, Claudio Macias-Trevino, Julia M. Rogers, Ryo Kurita, Yukio Nakamura, Guo Cheng Yuan, Daniel E. Bauer, Jian Xu, Martha L. Bulyk, Stuart H. Orkin

Research output: Contribution to journalArticle

51 Scopus citations

Abstract

Fetal hemoglobin (HbF, α2γ2) level is genetically controlled and modifies severity of adult hemoglobin (HbA, α2β2) disorders, sickle cell disease, and β-thalassemia. Common genetic variation affects expression of BCL11A, a regulator of HbF silencing. To uncover how BCL11A supports the developmental switch from γ- to β- globin, we use a functional assay and protein binding microarray to establish a requirement for a zinc-finger cluster in BCL11A in repression and identify a preferred DNA recognition sequence. This motif appears in embryonic and fetal-expressed globin promoters and is duplicated in γ-globin promoters. The more distal of the duplicated motifs is mutated in individuals with hereditary persistence of HbF. Using the CUT&RUN approach to map protein binding sites in erythroid cells, we demonstrate BCL11A occupancy preferentially at the distal motif, which can be disrupted by editing the promoter. Our findings reveal that direct γ-globin gene promoter repression by BCL11A underlies hemoglobin switching. The developmental transition between fetal and adult hemoglobin is controlled by a repressor that acts directly at the γ-globin gene promoter, suggesting a simplified control mechanism that could be manipulated in treatment of γ-hemoglobin disorders.

Original languageEnglish (US)
Pages (from-to)430-442.e17
JournalCell
Volume173
Issue number2
DOIs
Publication statusPublished - Apr 5 2018

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Keywords

  • BCL11A
  • CUT&RUN
  • digital genomic footprinting
  • DNA binding
  • gene editing
  • hemoglobin
  • protein-binding microarray
  • repression
  • zinc finger

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Liu, N., Hargreaves, V. V., Zhu, Q., Kurland, J. V., Hong, J., Kim, W., ... Orkin, S. H. (2018). Direct Promoter Repression by BCL11A Controls the Fetal to Adult Hemoglobin Switch. Cell, 173(2), 430-442.e17. https://doi.org/10.1016/j.cell.2018.03.016