Transcriptional silencing of γ-globin by BCL11A involves long-range interactions and cooperation with SOX6

Jian Xu, Vijay G. Sankaran, Min Ni, Tobias F. Menne, Rishi V. Puram, Woojin Kim, Stuart H. Orkin

Research output: Contribution to journalArticle

204 Citations (Scopus)

Abstract

The developmental switch from human fetal (γ) to adult (β) hemoglobin represents a clinically important example of developmental gene regulation. The transcription factor BCL11A is a central mediator of β-globin silencing and hemoglobin switching. Here we determine chromatin occupancy of BCL11A at the human β-globin locus and other genomic regions in vivo by high-resolution chromatin immunoprecipitation (ChIP)-chip analysis. BCL11A binds the upstream locus control region (LCR), ε-globin, and the intergenic regions between γ-globin and δ-globin genes. A chromosome conformation capture (3C) assay shows that BCL11A reconfigures the β-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 β-globin cluster along with GATA1, and cooperate in silencing γ-globin transcription in adult human erythroid progenitors. These findings collectively demonstrate that transcriptional silencing of γ-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 β-globin locus.

Original languageEnglish (US)
Pages (from-to)783-789
Number of pages7
JournalGenes and Development
Volume24
Issue number8
DOIs
StatePublished - Apr 15 2010

Fingerprint

Globins
Developmental Genes
SOXD Transcription Factors
Hemoglobins
Locus Control Region
Intergenic DNA
Chromatin Immunoprecipitation
Gene Silencing
Chromatin
Transcription Factors
Chromosomes

Keywords

  • BCL11A
  • Fetal hemoglobin
  • Hemoglobin switching
  • Transcription regulation

ASJC Scopus subject areas

  • Genetics
  • Developmental Biology
  • Medicine(all)

Cite this

Transcriptional silencing of γ-globin by BCL11A involves long-range interactions and cooperation with SOX6. / Xu, Jian; Sankaran, Vijay G.; Ni, Min; Menne, Tobias F.; Puram, Rishi V.; Kim, Woojin; Orkin, Stuart H.

In: Genes and Development, Vol. 24, No. 8, 15.04.2010, p. 783-789.

Research output: Contribution to journalArticle

Xu, Jian ; Sankaran, Vijay G. ; Ni, Min ; Menne, Tobias F. ; Puram, Rishi V. ; Kim, Woojin ; Orkin, Stuart H. / Transcriptional silencing of γ-globin by BCL11A involves long-range interactions and cooperation with SOX6. In: Genes and Development. 2010 ; Vol. 24, No. 8. pp. 783-789.
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