Th2 lineage commitment and efficient IL-4 production involves extended demethylation of the IL-4 gene

Immunity. 2002 May;16(5):649-60. doi: 10.1016/s1074-7613(02)00314-x.


The relation of CpG methylation to gene silencing is well established, but the contribution of DNA demethylation to gene expression during cell differentiation remains unclear. We show that the IL-4 locus undergoes a complex series of methylation and demethylation steps during T helper cell differentiation. The 5' region of the IL-4 locus is hypermethylated in naive T cells and becomes specifically demethylated in Th2 cells, whereas a highly conserved DNase I-hypersensitive region at the 3' end shows the converse behavior, being hypomethylated in naive T cells and becoming methylated during Th1 differentiation. 5' demethylation is not required for chromatin remodeling or primary transcription of the IL-4 gene but is strongly associated with efficient, high-level induction of IL-4 transcripts by differentiated Th2 cells.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Cell Differentiation
  • Cell Lineage
  • Cells, Cultured
  • Chromatin / metabolism
  • Clone Cells
  • CpG Islands*
  • DNA Methylation
  • DNA, Intergenic / metabolism
  • Interleukin-13 / genetics
  • Interleukin-4 / biosynthesis
  • Interleukin-4 / genetics*
  • Introns
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Promoter Regions, Genetic
  • RNA, Messenger / biosynthesis
  • Th1 Cells
  • Th2 Cells / immunology*
  • Transcriptional Activation*


  • Chromatin
  • DNA, Intergenic
  • Interleukin-13
  • RNA, Messenger
  • Interleukin-4