Transcription of Il17 and Il17f Is Controlled by Conserved Noncoding Sequence 2

Department of Immunology, M.D. Anderson Cancer Center, Houston, TX 77030, USA.
Immunity (Impact Factor: 21.56). 01/2012; 36(1):23-31. DOI: 10.1016/j.immuni.2011.10.019
Source: PubMed


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.

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    • "In addition, NR2F6 also directly competes with the Th17 lineage nuclear orphan receptor RORγt for the DNA accessibility to the hormone response elements within the Il17a conserved noncoding sequences (CNS)2 promoter region (Figure 2) [64,65]. Similar to NR2F6, the nuclear receptors RAR, PPAR, LXR, VDR, GR and ER repress Th17 differentiation and protect against the EAE disease mouse model. "
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