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Cell. 2018 Apr 5;173(2):430-442.e17. doi: 10.1016/j.cell.2018.03.016. Epub 2018 Mar 29.

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

Author information

1
Cancer and Blood Disorders Center, Dana Farber Cancer Institute and Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
2
Department of Biostatistics and Computational Biology, Dana Farber Cancer Institute and Harvard T.H. Chan School of Public Health, Boston, MA, USA.
3
Division of Genetics, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
4
Division of Genetics, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA; Committee on Higher Degrees in Biophysics, Harvard University, Cambridge, MA, USA.
5
Cell Engineering Division, RIKEN Bioresource Center, Tsukuba, Japan.
6
Children's Medical Center Research Institute, Department of Pediatrics, University of Texas at Southwestern Medical Center, Dallas, TX, USA.
7
Division of Genetics, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA; Committee on Higher Degrees in Biophysics, Harvard University, Cambridge, MA, USA; Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
8
Cancer and Blood Disorders Center, Dana Farber Cancer Institute and Boston Children's Hospital, Harvard Medical School, Boston, MA, USA; Howard Hughes Medical Institute, Boston, MA, USA. Electronic address: stuart_orkin@dfci.harvard.edu.

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.

KEYWORDS:

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

PMID:
29606353
PMCID:
PMC5889339
[Available on 2019-04-05]
DOI:
10.1016/j.cell.2018.03.016

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