Th2 lineage commitment and efficient IL-4 production involves extended demethylation of the IL-4 gene.
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.
Lee
Dong U
DU
Department of Pathology, Harvard Medical School and The Center for Blood Research, Boston, MA 02115, USA.
Agarwal
Suneet
S
Rao
Anjana
A
D000818:Animals; D002454:Cell Differentiation; D019070:Cell Lineage; D002478:Cells, Cultured; D002843:Chromatin / Q000378:metabolism; D002999:Clone Cells; D018899:CpG Islands; D019175:DNA Methylation; D021901:DNA, Intergenic / Q000378:metabolism; D018793:Interleukin-13 / Q000235:genetics; D015847:Interleukin-4 / Q000096:biosynthesis / Q000235:genetics*; D007438:Introns; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000096:biosynthesis; D018417:Th1 Cells; D018418:Th2 Cells / Q000276:immunology*; D015533:Transcriptional Activation
D002843:Chromatin; D021901:DNA, Intergenic; D018793:Interleukin-13; D012333:RNA, Messenger; D015847:Interleukin-4