Basal chromatin modification at the IL-4 gene in helper T cells.
Chromatin immunoprecipitations in naive CD4, but not CD8, T cells, demonstrated association of the IL-4 promoter with acetylated histone. Histone modifications and rapid IL-4 transcription were absent in conserved noncoding sequence 1 (CNS-1)(-/-) cells lacking an 8-kb-distant enhancer in the IL-4/IL-13 intergenic region, but also in CD4(-/-) and Itk(-/-) cells, which have similar Th2 deficiencies. Histones associated with the IL-13 promoter were not similarly acetylated in naive T cells, but became acetylated in differentiated Th2 cells. Conversely, Th1 differentiation induced histone methylation at the type 2 cytokine locus. Like CD4(-/-) and Itk(-/-) mice, CNS-1(-/-) BALB/c mice were highly resistant to the Th2-inducing protozoan, Leishmania major. CNS-1 deficiency led to failure of IL-4 gene repositioning to heterochromatin after Th1 polarization, possibly related to the presence of reiterative Ikaros binding sites in the intergenic element. Hyperacetylation of nonexpressed genes may serve to mark lineage-specific loci for rapid expression and further modification.
Grogan
Jane L
JL
Howard Hughes Medical Institute, Department of Medicine and Microbiology/Immunology, University of California, San Francisco, CA 94143- 0654, USA.
Wang
Zhi-En
ZE
Stanley
Sarah
S
Harmon
Brian
B
Loots
Gaby G
GG
Rubin
Edward M
EM
Locksley
Richard M
RM
D000818:Animals; D001483:Base Sequence; D001665:Binding Sites / Q000235:genetics; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D002460:Cell Line; D002478:Cells, Cultured; D002843:Chromatin / Q000378:metabolism*; D017124:Conserved Sequence / Q000235:genetics / Q000276:immunology; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D021901:DNA, Intergenic / Q000276:immunology; D004268:DNA-Binding Proteins; D004742:Enhancer Elements, Genetic; D005260:Female; D005819:Genetic Markers; D020022:Genetic Predisposition to Disease; D006570:Heterochromatin / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D051740:Ikaros Transcription Factor; D007113:Immunity, Innate / Q000235:genetics; D015847:Interleukin-4 / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism*; D016773:Leishmaniasis, Cutaneous / Q000235:genetics / Q000276:immunology; D008213:Lymphocyte Activation / Q000235:genetics; D008407:Mast Cells / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology* / Q000378:metabolism*; D018418:Th2 Cells / Q000276:immunology / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
D002843:Chromatin; D016207:Cytokines; D021901:DNA, Intergenic; D004268:DNA-Binding Proteins; D005819:Genetic Markers; D006570:Heterochromatin; D006657:Histones; D014157:Transcription Factors; C497238:Zfpn1a1 protein, mouse; D051740:Ikaros Transcription Factor; D015847:Interleukin-4