Comprehensive epigenetic profiling identifies multiple distal regulatory elements directing transcription of the gene encoding interferon-gamma.
Unlike the well defined T helper type 2 cytokine locus, little is known about the regulatory elements that govern the expression of Ifng, which encodes the 'signature' T helper type 1 cytokine interferon-gamma. Here our evolutionary analysis showed that the mouse Ifng locus diverged from the ancestral locus as a result of structural rearrangements producing deletion of the neighboring gene encoding interleukin 26 and disrupting synteny 57 kilobases upstream of Ifng. Proximal to that disruption, we identified by high-resolution mapping many regions with CD4+ T cell subset-specific epigenetic modifications. A subset of those regions represented enhancers, whereas others blocked the activity of upstream enhancers or insulated Ifng from neighboring chromatin. Our findings suggest that proper expression of Ifng is maintained through the collective action of multiple distal regulatory elements present in a region of about 100 kilobases flanking Ifng.
Schoenborn
Jamie R
JR
Department of Immunology, University of Washington, Seattle, Washington 98195, USA.
Dorschner
Michael O
MO
Sekimata
Masayuki
M
Santer
Deanna M
DM
Shnyreva
Maria
M
Fitzpatrick
David R
DR
Stamatoyannopoulos
John A
JA
Stamatoyonnapoulos
John A
JA
Wilson
Christopher B
CB
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism*; D002460:Cell Line; D017124:Conserved Sequence; D019175:DNA Methylation; D044127:Epigenesis, Genetic / Q000276:immunology*; D020869:Gene Expression Profiling; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D050436:Regulatory Elements, Transcriptional / Q000276:immunology*; D014158:Transcription, Genetic / Q000276:immunology; D014407:Tumor Cells, Cultured
D007371:Interferon-gamma