title: Transcription of Il17 and Il17f is controlled by conserved noncoding sequence 2.
abstract: T helper 17 (Th17) cells specifically transcribe the Il17 and Il17f genes, which are localized in the same chromosome region, but the underlying mechanism is unclear. Here, we report a cis element that we previously named conserved noncoding sequence 2 (CNS2) physically interacted with both Il17 and Il17f gene promoters and was sufficient for regulating their selective transcription in Th17 cells. Targeted deletion of CNS2 resulted in impaired retinoic acid-related orphan receptor gammat (RORγt)-driven IL-17 expression in vitro. CNS2-deficient T cells also produced substantially decreased amounts of IL-17F. These cytokine defects were associated with defective chromatin remodeling in the Il17-Il17f gene locus, possibly because of effects on CNS2-mediated recruitment of histone-modifying enzymes p300 and JmjC domain-containing protein 3 (JMJD3). CNS2-deficient animals were also shown to be resistant to experimental autoimmune encephalomyelitis (EAE). Our results thus suggest that CNS2 is sufficient and necessary for Il17 and optimal Il17f gene transcription in Th17 cells.
authors.affiliation: Department of Immunology, M.D. Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Xiaohu
authors.initials: X
authors.lastname: Wang
authors.forename: Yibing
authors.initials: Y
authors.lastname: Zhang
authors.forename: Xuexian O
authors.initials: XO
authors.lastname: Yang
authors.forename: Roza I
authors.initials: RI
authors.lastname: Nurieva
authors.forename: Seon Hee
authors.initials: SH
authors.lastname: Chang
authors.forename: Sandra S
authors.initials: SS
authors.lastname: Ojeda
authors.forename: Hong S
authors.initials: HS
authors.lastname: Kang
authors.forename: Kimberly S
authors.initials: KS
authors.lastname: Schluns
authors.forename: Jianfang
authors.initials: J
authors.lastname: Gui
authors.forename: Anton M
authors.initials: AM
authors.lastname: Jetten
authors.forename: Chen
authors.initials: C
authors.lastname: Dong
mesh_terms: D000818:Animals; D017124:Conserved Sequence; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000235:genetics; D005786:Gene Expression Regulation; D020381:Interleukin-17 / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D011401:Promoter Regions, Genetic; D058727:RNA, Small Untranslated; D060888:Real-Time Polymerase Chain Reaction; D050436:Regulatory Elements, Transcriptional
chemical_list: D020381:Interleukin-17; D058727:RNA, Small Untranslated