An intronic enhancer driven by NF-κB contributes to transcriptional regulation of peptidylarginine deiminase type I gene in human keratinocytes.

Peptidylarginine deiminases catalyze the conversion of protein-bound arginine to citrulline residues. In human epidermis, where filaggrin is the main deiminated protein, three are detected with specific patterns of expression depending on the keratinocyte (KC) differentiation state. Previous characterizations of the gene promoters have shown that proximal regulation alone is not sufficient to explain this specificity of expression. In this work, we describe an evolutionarily highly conserved nucleotide segment located in the first intron of the gene Luciferase reporter assays showed that it enhances the activity of the promoter, in a calcium- and orientation-independent manner. Mutation of a putative NF-κB cis-element markedly reduced its enhancer activity, which also confirmed its potential regulatory function. Chromatin immunoprecipitation assays evidenced the binding of both p65 and p50 NF-κB subunits to the cis-element, and RNA interference inhibition assays confirmed that NF-κB contributes to the duanyu1563I1 transcriptional control. Furthermore, the intronic enhancer and promoter of duanyu1563I1 potentially interact through chromatin looping, as indicated by chromosome conformation capture assays. Our findings provide evidence that an NF-κB-mediated signaling pathway is involved in duanyu1563I1 regulation in human epidermal KCs.

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