Transcriptional silencing of {gamma}-globin by BCL11A involves long-range interactions and cooperation with SOX6.
The developmental switch from human fetal (gamma) to adult (beta) hemoglobin represents a clinically important example of developmental gene regulation. The transcription factor BCL11A is a central mediator of gamma-globin silencing and hemoglobin switching. Here we determine chromatin occupancy of BCL11A at the human beta-globin locus and other genomic regions in vivo by high-resolution chromatin immunoprecipitation (ChIP)-chip analysis. BCL11A binds the upstream locus control region (LCR), epsilon-globin, and the intergenic regions between gamma-globin and delta-globin genes. A chromosome conformation capture (3C) assay shows that BCL11A reconfigures the beta-globin cluster by modulating chromosomal loop formation. We also show that BCL11A and the HMG-box-containing transcription factor SOX6 interact physically and functionally during erythroid maturation. BCL11A and SOX6 co-occupy the human beta-globin cluster along with GATA1, and cooperate in silencing gamma-globin transcription in adult human erythroid progenitors. These findings collectively demonstrate that transcriptional silencing of gamma-globin genes by BCL11A involves long-range interactions and cooperation with SOX6. Our findings provide insight into the mechanism of BCL11A action and new clues for the developmental gene regulatory programs that function at the beta-globin locus.
Xu
Jian
J
Children's Hospital Boston, Massachusetts 02115, USA.
Sankaran
Vijay G
VG
Ni
Min
M
Menne
Tobias F
TF
Puram
Rishi V
RV
Kim
Woojin
W
Orkin
Stuart H
SH
D000328:Adult; D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism*; D002460:Cell Line; D041905:Erythroid Cells / Q000166:cytology / Q000378:metabolism*; D004920:Erythropoiesis / Q000502:physiology; D050982:GATA1 Transcription Factor / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D020868:Gene Silencing; D006657:Histones / Q000378:metabolism; D006801:Humans; D051379:Mice; D009687:Nuclear Proteins / Q000378:metabolism*; D011485:Protein Binding; D021381:Protein Transport; D012097:Repressor Proteins; D055755:SOXD Transcription Factors / Q000378:metabolism*; D055545:gamma-Globins / Q000378:metabolism*
C486563:BCL11A protein, human; D002352:Carrier Proteins; D050982:GATA1 Transcription Factor; C494688:GATA1 protein, human; D006657:Histones; D009687:Nuclear Proteins; D012097:Repressor Proteins; C486270:SOX6 protein, human; D055755:SOXD Transcription Factors; D055545:gamma-Globins
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