PhD Student Karolinska Institutet Solna, Stockholms Lan, Sweden
Abstract: Citrullination is a post-translational modification catalyzed by the Peptidyl Arginine Deiminase (PADI) enzyme family. By altering the charge of histone tails, citrullination modulates chromatin compaction, orchestrating transcriptional programs epigenetically when occurring at gene regulatory regions. Conversely, global histone citrullination promotes chromatin condensation and extracellular trap formation, contributing to programmed cell death such as NETosis. Over the years, histone citrullination has been implicated in a broad spectrum of biological processes, such as pluripotency maintenance, cell fate determination, cancer progression, and autoimmunity, highlighting its vast biological significance. Despite the structural and functional similarities among Padi enzymes and their nuclear localization, the epigenetic roles of certain members, such as Padi3, remain unexplored. Interestingly, our Proximity Ligation Assay (PLA) result revealed that Padi3 interacts with histone H3 in mouse epidermal progenitor cells primarily in the nucleus, while immunoblotting demonstrated forced Padi3 expression leads to H3 hypercitrullination in human embryonic kidney cells (HEK 293). These results strongly implicate Padi3 in epigenetic regulation, a novel and unknown function. To elucidate the mechanisms underlying Padi3-mediated gene regulation, we will employ Chromatin Immunoprecipitation (ChIP) and SLAM-sequencing to identify direct gene targets, while biochemical assays will investigate its interactions with other Padi enzymes and chromatin regulators. Collectively, this study aims to expand our understanding of the epigenetic functions of Padi3 and pave the way for future research into its role in a wide range of normal biological processes and diseases.
