Gene Regulation at a Distance in the Epidermal Keratinocyte: The Paradigm of the PADI Gene Locus

Long-range cis elements are critical regulators of gene transcription, particularly for paralogous genes clustered on a unique chromosomal region. Such are the five PADI genes in 1p35–36 encoding peptidylarginine deiminases. These enzymes catalyze deimination, or citrullination, a calcium-dependent post-translational modification of proteins which has been implicated in gene regulation and in the pathophysiology of multiple sclerosis and rheumatoid arthritis. The epidermis is an exciting model for understanding PADI gene regulation since only the genes PADI1–3 are expressed in the epidermal keratinocytes, with increased expression levels in the most differentiated cells. Studies on PADI proximal promoters failed to explain such a specificity of expression. Here, we describe long-range regulatory elements identified as essential for the PADI3 specific expression in differentiated keratinocytes through the formation of a chromatin loop.