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

33 Citations (Scopus)

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
StatePublished - Apr 5 2018

Fingerprint

Globins
Hemoglobins
Switches
Fetal Hemoglobin
Protein Binding
Genes
Protein Array Analysis
Erythroid Cells
Thalassemia
Zinc Fingers
Sickle Cell Anemia
Microarrays
Zinc
Assays
Binding Sites
DNA

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

Direct Promoter Repression by BCL11A Controls the Fetal to Adult Hemoglobin Switch. / Liu, Nan; Hargreaves, Victoria V.; Zhu, Qian; Kurland, Jesse V.; Hong, Jiyoung; Kim, Woojin; Sher, Falak; Macias-Trevino, Claudio; Rogers, Julia M.; Kurita, Ryo; Nakamura, Yukio; Yuan, Guo Cheng; Bauer, Daniel E.; Xu, Jian; Bulyk, Martha L.; Orkin, Stuart H.

In: Cell, Vol. 173, No. 2, 05.04.2018, p. 430-442.e17.

Research output: Contribution to journalArticle

Liu, N, Hargreaves, VV, Zhu, Q, Kurland, JV, Hong, J, Kim, W, Sher, F, Macias-Trevino, C, Rogers, JM, Kurita, R, Nakamura, Y, Yuan, GC, Bauer, DE, Xu, J, Bulyk, ML & Orkin, SH 2018, 'Direct Promoter Repression by BCL11A Controls the Fetal to Adult Hemoglobin Switch', Cell, vol. 173, no. 2, pp. 430-442.e17. https://doi.org/10.1016/j.cell.2018.03.016
Liu N, Hargreaves VV, Zhu Q, Kurland JV, Hong J, Kim W et al. Direct Promoter Repression by BCL11A Controls the Fetal to Adult Hemoglobin Switch. Cell. 2018 Apr 5;173(2):430-442.e17. https://doi.org/10.1016/j.cell.2018.03.016
Liu, Nan ; Hargreaves, Victoria V. ; Zhu, Qian ; Kurland, Jesse V. ; Hong, Jiyoung ; Kim, Woojin ; Sher, Falak ; Macias-Trevino, Claudio ; Rogers, Julia M. ; Kurita, Ryo ; Nakamura, Yukio ; Yuan, Guo Cheng ; Bauer, Daniel E. ; Xu, Jian ; Bulyk, Martha L. ; Orkin, Stuart H. / Direct Promoter Repression by BCL11A Controls the Fetal to Adult Hemoglobin Switch. In: Cell. 2018 ; Vol. 173, No. 2. pp. 430-442.e17.
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