Reactivation of developmentally silenced globin genes by forced chromatin looping

Cell. 2014 Aug 14;158(4):849-860. doi: 10.1016/j.cell.2014.05.050.


Distal enhancers commonly contact target promoters via chromatin looping. In erythroid cells, the locus control region (LCR) contacts β-type globin genes in a developmental stage-specific manner to stimulate transcription. Previously, we induced LCR-promoter looping by tethering the self-association domain (SA) of Ldb1 to the β-globin promoter via artificial zinc fingers. Here, we show that targeting the SA to a developmentally silenced embryonic globin gene in adult murine erythroblasts triggers its transcriptional reactivation. This activity depends on the LCR, consistent with an LCR-promoter looping mechanism. Strikingly, targeting the SA to the fetal γ-globin promoter in primary adult human erythroblasts increases γ-globin promoter-LCR contacts, stimulating transcription to approximately 85% of total β-globin synthesis, with a reciprocal reduction in adult β-globin expression. Our findings demonstrate that forced chromatin looping can override a stringent developmental gene expression program and suggest a novel approach to control the balance of globin gene transcription for therapeutic applications.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigens, CD34 / metabolism
  • Chromatin / chemistry
  • Chromatin / metabolism*
  • Embryo, Mammalian / metabolism
  • Erythroblasts / metabolism
  • Fetal Hemoglobin / genetics*
  • Genetic Techniques*
  • Hemoglobinopathies / genetics
  • Hemoglobinopathies / therapy
  • Humans
  • Locus Control Region*
  • Mice
  • Primary Cell Culture
  • Transcriptional Activation*
  • beta-Globins / genetics*


  • Antigens, CD34
  • Chromatin
  • beta-Globins
  • Fetal Hemoglobin