Intron-1 rs3761548 is related to the defective transcription of  Foxp3 in psoriasis through abrogating E47/c-Myb binding.
Foxp3 is a master transcription factor (TF) for development and function of CD4(+)CD25(+)Foxp3(+) regulatory T cells (Treg cells) and is critical for the transcription of target genes. But the transcriptional regulation of Foxp3 itself has not been fully understood until now. Here, we aimed to demonstrate the hypothesis that upstream single nucleotide polymorphism(s) (SNPs) of Foxp3 was/were responsible for the defective transcription of Foxp3 in psoriasis and to explore the mechanism behind this hypothesis. In this study, SNP of large sample was investigated for risk analysis. Mature algorithms, electrophoretic mobility shift and chromatin immunoprecipitation assays were used to identify TF binding site variations. Loss-of-function and overexpression assays and cell cycle blocker assay were performed to identify when and what kind of possible roles the candidate factors play. Our results showed that intron-1 rs3761548 was correlated with a significant susceptibility to psoriasis. The rs3761548 contributed to the decreased resting Foxp3 transcription and impaired acceleration of Foxp3 transcription levels after stimulation in psoriatic patients with genotype AA. We analysed and demonstrated potent new E47/c-Myb -dependent regulation elements in rs3761548, oppositely controlling Foxp3 gene transcription at G1 and G2/M phases of Treg cells in psoriatic patients. For patients with rs3761548 AA, the polymorphism causes loss of bindings to the E47 and c-Myb factors, leading to defective transcription of Foxp3 gene. Further identification of the networks and molecular mechanisms underlying Foxp3 transcription may provide new insights into Foxp3 transcriptional regulation and alternative therapeutic strategies to improve characteristics of autoimmune disorders.
Shen
Z
Z
Department of Dermatology, Southwest Hospital, Third Military Medical University, Chongqing, China. shenzhuxa@gmail.com
Chen
L
L
Hao
F
F
Wang
G
G
Liu
Y
Y