Human fetal globin gene expression is regulated by LYAR

Nucleic Acids Res. 2014 Sep;42(15):9740-52. doi: 10.1093/nar/gku718. Epub 2014 Aug 4.


Human globin gene expression during development is modulated by transcription factors in a stage-dependent manner. However, the mechanisms controlling the process are still largely unknown. In this study, we found that a nuclear protein, LYAR (human homologue of mouse Ly-1 antibody reactive clone) directly interacted with the methyltransferase PRMT5 which triggers the histone H4 Arg3 symmetric dimethylation (H4R3me2s) mark. We found that PRMT5 binding on the proximal γ-promoter was LYAR-dependent. The LYAR DNA-binding motif (GGTTAT) was identified by performing CASTing (cyclic amplification and selection of targets) experiments. Results of EMSA and ChIP assays confirmed that LYAR bound to a DNA region corresponding to the 5'-untranslated region of the γ-globin gene. We also found that LYAR repressed human fetal globin gene expression in both K562 cells and primary human adult erythroid progenitor cells. Thus, these data indicate that LYAR acts as a novel transcription factor that binds the γ-globin gene, and is essential for silencing the γ-globin gene.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 5' Untranslated Regions
  • Animals
  • Base Sequence
  • Cell Differentiation / genetics
  • Cells, Cultured
  • Consensus Sequence
  • DNA-Binding Proteins / antagonists & inhibitors
  • DNA-Binding Proteins / metabolism*
  • DNA-Binding Proteins / physiology
  • Erythroid Cells / cytology
  • Erythroid Cells / metabolism
  • Gene Expression Regulation, Developmental*
  • Gene Silencing
  • Humans
  • K562 Cells
  • Mice
  • Nuclear Proteins / antagonists & inhibitors
  • Nuclear Proteins / metabolism*
  • Nuclear Proteins / physiology
  • Protein-Arginine N-Methyltransferases / metabolism
  • Repressor Proteins / metabolism
  • gamma-Globins / genetics*
  • gamma-Globins / metabolism


  • 5' Untranslated Regions
  • DNA-Binding Proteins
  • LYAR protein, human
  • Lyar protein, mouse
  • Nuclear Proteins
  • Repressor Proteins
  • gamma-Globins
  • PRMT5 protein, human
  • Protein-Arginine N-Methyltransferases