Peptidylarginine deiminase 4 (PADI4),a new histone modification enzyme,which converts both arginine and monomethyl-arginine to citrulline,has gained massive attention in recent years as a potential regulator of gene transcription.Recent studies have shown that arginine residues R2,R8,R17,and R26 in the H3 tail and R3 in the H4 tail can be deiminated by PADI4.This kind of histone post-translational modification has the potential to antagonize histone methylation and coordinate with histone deacetylation to regulate gene transcription.PADI4 also deiminates non-histone proteins,such as p300,NPM1,ING4,RPS2,and DNMT3A.PADI4 has been shown to involve in cell apoptosis and differentiation.Moreover,PADI4 can interact with tumor suppressor p53 and regulate the transcriptional activity of p53.Dysregulation of PADI4 is implicated in a variety of diseases,including rheumatoid arthritis,tumor development,and multiple sclerosis.A wide variety of PADI4 inhibitors have been identified.Further understanding of PADI4 functions may lead to novel diagnostic and therapeutic approaches in these diseases.This review summarizes the recent progress in the study of the regulation mechanism of PADI4 on gene transcription and the major physiological functions of PADI4 in human diseases.