Chromatin-based regulation of cytokine transcription in Th2 cells and mast cells.
Th2 cells and mast cells are major sources of IL4, IL5 and IL13, cytokines that mediate immunity against parasites and are also central players in the pathophysiology of asthma, allergy and atopic disease. We asked whether Th2 cells and mast cells, which belong to the lymphoid and myeloid lineages, respectively, use different cis-acting regulatory regions to transcribe the cytokine genes. Comparison of DNase I hypersensitivity patterns at the RAD50/IL4/IL13 locus revealed that most hypersensitive sites (HSs) are common to Th2 and mast cells, but two regions [conserved non-coding sequence (CNS) 1 and mast cell HSs] show cell type-specific differences. CNS-1, one of the most highly conserved CNS regions in the RAD50/IL13/IL4 locus, displays two strong DNase I HSs in Th2 cells but is not DNase I hypersensitive in mast cells, explaining a previous finding that deletion of CNS-1 impairs cytokine expression in Th2 cells but not in mast cells. Conversely, two constitutive HSs (mast cell HSs) in the first intron of the IL13 gene are present in mast cells but not in Th2 cells; these sites develop early during mast cell differentiation and may have a role in maintaining accessibility of the IL13 locus to high-level transcription in stimulated cells.
Monticelli
Silvia
S
Department of Pathology, Harvard Medical School, and CBR Institute for Biomedical Research, Boston, MA 02115, USA.
Lee
Dong U
DU
Nardone
Julie
J
Bolton
Diana L
DL
Rao
Anjana
A
D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000276:immunology; D017766:Acid Anhydride Hydrolases; D000818:Animals; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology*; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis* / Q000235:genetics / Q000276:immunology; D004268:DNA-Binding Proteins; D005786:Gene Expression Regulation / Q000235:genetics / Q000276:immunology*; D008407:Mast Cells / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D040641:Quantitative Trait Loci / Q000235:genetics / Q000276:immunology; D012045:Regulatory Sequences, Nucleic Acid / Q000235:genetics / Q000276:immunology; D018418:Th2 Cells / Q000276:immunology*; D014158:Transcription, Genetic / Q000235:genetics / Q000276:immunology
D018528:ATP-Binding Cassette Transporters; D016207:Cytokines; D004268:DNA-Binding Proteins; D017766:Acid Anhydride Hydrolases; C495198:Rad50 protein, mouse