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<p>Individual enhancers are defined as short genomic regulatory elements, bound by transcription factors, and able to activate cell-specific gene expression at a distance, in an orientation-independent manner. Within mammalian genomes, enhancer-like elements may be found individually or within clusters referred to as locus control regions or super-enhancers (SEs). While these behave similarly to individual enhancers with respect to cell specificity, distribution and distance, their orientation-dependence has not been formally tested. Here, using the α-globin locus as a model, we show that while an individual enhancer works in an orientation-independent manner, the direction of activity of a SE changes with its orientation. When the SE is inverted within its normal chromosomal context, expression of its normal targets, the α-globin genes, is severely reduced and the normally silent genes lying upstream of the α-globin locus are upregulated. These findings add to our understanding of enhancer-promoter specificity that precisely activate transcription.</p>

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The α-globin super-enhancer acts in an orientation-dependent manner

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年1月25日

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  • Mira T. Kassouf,
  • Helena S. Francis,
  • Matthew Gosden,
  • Maria C. Suciu,
  • Damien J. Downes,
  • Caroline Harrold,
  • Martin Larke,
  • Marieke Oudelaar,
  • Lucy Cornell,
  • Joseph Blayney,
  • Jelena Telenius,
  • Barbara Xella,
  • Yuki Shen,
  • Nikolaos Sousos,
  • Jacqueline A. Sharpe,
  • Jacqueline Sloane-Stanley,
  • Andrew J. H. Smith,
  • Christian Babbs,
  • Jim R. Hughes,
  • Douglas R. Higgs

摘要

Individual enhancers are defined as short genomic regulatory elements, bound by transcription factors, and able to activate cell-specific gene expression at a distance, in an orientation-independent manner. Within mammalian genomes, enhancer-like elements may be found individually or within clusters referred to as locus control regions or super-enhancers (SEs). While these behave similarly to individual enhancers with respect to cell specificity, distribution and distance, their orientation-dependence has not been formally tested. Here, using the α-globin locus as a model, we show that while an individual enhancer works in an orientation-independent manner, the direction of activity of a SE changes with its orientation. When the SE is inverted within its normal chromosomal context, expression of its normal targets, the α-globin genes, is severely reduced and the normally silent genes lying upstream of the α-globin locus are upregulated. These findings add to our understanding of enhancer-promoter specificity that precisely activate transcription.