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. Author manuscript; available in PMC: 2021 Jul 7.
Published in final edited form as: Cytokine. 2021 Mar 13;142:155491. doi: 10.1016/j.cyto.2021.155491

Fig. 7. Schematic representation and summary of the results of this study.

Fig. 7

The top panel shows the IFN-λ3 promoter with the different TF binding sites identified in the context of the three functional genetic variants studied. A) Our results show that IRF7 (or IRF3) binding to its DNA is rate-limiting on the IFN-λ3 promoter. Binding of NF-κB p65 (as a hetero or a homodimer) enhances the promoter occupancy of IRF7 possibly by causing allosteric changes to the IRF-binding site DNA and allowing for a better access of IRF7 into the major groove of the DNA thereby overcoming the rate-limiting step in promoter loading. This may occur without any protein-protein contacts between IRF7 and p65; or may involve such contacts in a long-range over the promoter that somehow brings the distantly bound TFs in proximity in the 3-D conformation (B); however, we feel that this model (B) is less likely to lead to promote synergy at the IFN-λ3 promoter. C) The mechanism behind the functioning of the TA repeat polymorphism in affecting IRF7-mediated transcription. The changes in the DNA helix phase disrupts IRF7 binding since IRF7 binding seems to be sensitive to such changes as extensive contacts between a well-structured protein region (in the form of a short alpha-helix) with the nucleotides within the major grove (red) are observed in the co-crystal structures. Every two TA repeats increases the nucleotide length by 4 which is close to half the number of bases that lead to a turn of the DNA helix, thereby disrupting the helix such that bases in the major groove are now in the minor grove and therefore IRF7 finds it difficult to tuck its short alpha-helix into the minor grove in the new phase. This leads to a cyclical effect on transcription (dashed line) as the next two TA repeats can partially restore the helix phase. D) Three functional genetic variants of the IFN-λ3 promoter: rs28416813, rs4803217 and TA-repeat polymorphism (rs7225881). SNP rs28416813 affects NF-κB binding near the basal transcription apparatus (RNA pol) and SNP rs4803217 interferes with miRNA binding and the mRNA stability while present in the 3’UTR of the mRNA. The ancestral alleles of both these SNPs significantly decrease gene expression. The TA-repeat polymorphism affects DNA phasing and therefore likely affects IRF7-mediated transcription.