title: Histone hypercitrullination mediates chromatin decondensation and neutrophil extracellular trap formation.
abstract: Peripheral blood neutrophils form highly decondensed chromatin structures, termed neutrophil extracellular traps (NETs), that have been implicated in innate immune response to bacterial infection. Neutrophils express high levels of peptidylarginine deiminase 4 (PAD4), which catalyzes histone citrullination. However, whether PAD4 or histone citrullination plays a role in chromatin structure in neutrophils is unclear. In this study, we show that the hypercitrullination of histones by PAD4 mediates chromatin decondensation. Histone hypercitrullination is detected on highly decondensed chromatin in HL-60 granulocytes and blood neutrophils. The inhibition of PAD4 decreases histone hypercitrullination and the formation of NET-like structures, whereas PAD4 treatment of HL-60 cells facilitates these processes. The loss of heterochromatin and multilobular nuclear structures is detected in HL-60 granulocytes after PAD4 activation. Importantly, citrullination of biochemically defined avian nucleosome arrays inhibits their compaction by the linker histone H5 to form higher order chromatin structures. Together, these results suggest that histone hypercitrullination has important functions in chromatin decondensation in granulocytes/neutrophils.
authors.affiliation: Center for Gene Regulation, Department of Biochemistry and Molecular Biology, Pennsylvania State University, University Park, PA 16802, USA. yuw12@psu.edu
authors.forename: Yanming
authors.initials: Y
authors.lastname: Wang
authors.forename: Ming
authors.initials: M
authors.lastname: Li
authors.forename: Sonja
authors.initials: S
authors.lastname: Stadler
authors.forename: Sarah
authors.initials: S
authors.lastname: Correll
authors.forename: Pingxin
authors.initials: P
authors.lastname: Li
authors.forename: Danchen
authors.initials: D
authors.lastname: Wang
authors.forename: Ryo
authors.initials: R
authors.lastname: Hayama
authors.forename: Lauriebeth
authors.initials: L
authors.lastname: Leonelli
authors.forename: Hyunsil
authors.initials: H
authors.lastname: Han
authors.forename: Sergei A
authors.initials: SA
authors.lastname: Grigoryev
authors.forename: C David
authors.initials: CD
authors.lastname: Allis
authors.forename: Scott A
authors.initials: SA
authors.lastname: Coonrod
mesh_terms: D002843:Chromatin / Q000378:metabolism*; D002956:Citrulline / Q000378:metabolism; D006098:Granulocytes / Q000378:metabolism; D018922:HL-60 Cells; D006657:Histones / Q000378:metabolism*; D006801:Humans; D006867:Hydrolases / Q000378:metabolism; D009504:Neutrophils / Q000378:metabolism / Q000648:ultrastructure*; D000080002:Protein-Arginine Deiminase Type 4; D000076342:Protein-Arginine Deiminases; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D002843:Chromatin; D006657:Histones; D014409:Tumor Necrosis Factor-alpha; D002956:Citrulline; D006867:Hydrolases; C000629235:PADI4 protein, human; D000080002:Protein-Arginine Deiminase Type 4; D000076342:Protein-Arginine Deiminases