title: Homocitrullination Is a Novel Histone H1 Epigenetic Mark Dependent on Aryl Hydrocarbon Receptor Recruitment of Carbamoyl Phosphate Synthase 1.
abstract: The aryl hydrocarbon receptor (AhR), a regulator of xenobiotic toxicity, is a member of the eukaryotic Per-Arnt-Sim domain protein family of transcription factors. Recent evidence identified a novel AhR DNA recognition sequence called the nonconsensus xenobiotic response element (NC-XRE). AhR binding to the NC-XRE in response to activation by the canonical ligand 2,3,7,8-tetrachlorodibenzo-p-dioxin resulted in concomitant recruitment of carbamoyl phosphate synthase 1 (CPS1) to the NC-XRE. Studies presented here demonstrate that CPS1 is a bona fide nuclear protein involved in homocitrullination (hcit), including a key lysine residue on histone H1 (H1K34hcit). H1K34hcit represents a hitherto unknown epigenetic mark implicated in enhanced gene expression of the peptidylarginine deiminase 2 gene, itself a chromatin-modifying protein. Collectively, our data suggest that AhR activation promotes CPS1 recruitment to DNA enhancer sites in the genome, resulting in a specific enzyme-independent post-translational modification of the linker histone H1 protein (H1K34hcit), pivotal in altering local chromatin structure and transcriptional activation.
authors.affiliation: From the Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, Texas 77555 and.
authors.forename: Aditya D
authors.initials: AD
authors.lastname: Joshi
authors.affiliation: Protea, Morgantown, West Virginia 26505.
authors.forename: Mehnaz G
authors.initials: MG
authors.lastname: Mustafa
authors.affiliation: From the Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, Texas 77555 and.
authors.forename: Cheryl F
authors.initials: CF
authors.lastname: Lichti
authors.affiliation: From the Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, Texas 77555 and coelferi@utmb.edu.
authors.forename: Cornelis J
authors.initials: CJ
authors.lastname: Elferink
mesh_terms: D000818:Animals; D001483:Base Sequence; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism*; D002222:Carbamoyl-Phosphate Synthase (Ammonia) / Q000378:metabolism*; D002478:Cells, Cultured; D002843:Chromatin / Q000378:metabolism / Q000648:ultrastructure; D002956:Citrulline / Q000031:analogs & derivatives* / Q000378:metabolism; D044127:Epigenesis, Genetic; D005260:Female; D006657:Histones / Q000378:metabolism*; D006867:Hydrolases / Q000235:genetics; D008239:Lysine / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009687:Nuclear Proteins / Q000378:metabolism*; D000072317:Polychlorinated Dibenzodioxins / Q000378:metabolism; D011485:Protein Binding; D011499:Protein Processing, Post-Translational; D017434:Protein Structure, Tertiary; D000076342:Protein-Arginine Deiminases; D018336:Receptors, Aryl Hydrocarbon / Q000378:metabolism*; D020218:Response Elements; D015533:Transcriptional Activation
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D002222:Carbamoyl-Phosphate Synthase (Ammonia); D002843:Chromatin; D002956:Citrulline; D006657:Histones; D006867:Hydrolases; D008239:Lysine; D009687:Nuclear Proteins; D000072317:Polychlorinated Dibenzodioxins; D000076342:Protein-Arginine Deiminases; D018336:Receptors, Aryl Hydrocarbon; C484722:Ahr protein, mouse; C001352:homocitrulline
keywords: aryl hydrocarbon receptor (AhR) (AHR); chromatin modification; dioxin; gene regulation; hepatocyte