Controlling long-range genomic interactions at a native locus by targeted tethering of a looping factor

Cell. 2012 Jun 8;149(6):1233-44. doi: 10.1016/j.cell.2012.03.051.


Chromatin loops juxtapose distal enhancers with active promoters, but their molecular architecture and relationship with transcription remain unclear. In erythroid cells, the locus control region (LCR) and β-globin promoter form a chromatin loop that requires transcription factor GATA1 and the associated molecule Ldb1. We employed artificial zinc fingers (ZF) to tether Ldb1 to the β-globin promoter in GATA1 null erythroblasts, in which the β-globin locus is relaxed and inactive. Remarkably, targeting Ldb1 or only its self-association domain to the β-globin promoter substantially activated β-globin transcription in the absence of GATA1. Promoter-tethered Ldb1 interacted with endogenous Ldb1 complexes at the LCR to form a chromatin loop, causing recruitment and phosphorylation of RNA polymerase II. ZF-Ldb1 proteins were inactive at alleles lacking the LCR, demonstrating that their activities depend on long-range interactions. Our findings establish Ldb1 as a critical effector of GATA1-mediated loop formation and indicate that chromatin looping causally underlies gene regulation.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural

MeSH terms

  • Animals
  • Cell Line
  • Cell Separation
  • Chromatin / metabolism*
  • DNA-Binding Proteins / chemistry
  • DNA-Binding Proteins / metabolism*
  • Embryo, Mammalian / cytology
  • Erythroblasts / metabolism
  • Female
  • GATA1 Transcription Factor / metabolism
  • Gene Expression Regulation
  • LIM Domain Proteins / chemistry
  • LIM Domain Proteins / metabolism*
  • Male
  • Mice
  • Promoter Regions, Genetic
  • Protein Structure, Tertiary
  • Transcription, Genetic*
  • Zinc Fingers
  • beta-Globins / genetics*


  • Chromatin
  • DNA-Binding Proteins
  • GATA1 Transcription Factor
  • Gata1 protein, mouse
  • LIM Domain Proteins
  • Ldb1 protein, mouse
  • beta-Globins