title: Peptidylarginine deiminase 2-catalyzed histone H3 arginine 26 citrullination facilitates estrogen receptor α target gene activation.
abstract: Cofactors for estrogen receptor α (ERα) can modulate gene activity by posttranslationally modifying histone tails at target promoters. Here, we found that stimulation of ERα-positive cells with 17β-estradiol (E2) promotes global citrullination of histone H3 arginine 26 (H3R26) on chromatin. Additionally, we found that the H3 citrulline 26 (H3Cit26) modification colocalizes with ERα at decondensed chromatin loci surrounding the estrogen-response elements of target promoters. Surprisingly, we also found that citrullination of H3R26 is catalyzed by peptidylarginine deiminase (PAD) 2 and not by PAD4 (which citrullinates H4R3). Further, we showed that PAD2 interacts with ERα after E2 stimulation and that inhibition of either PAD2 or ERα strongly suppresses E2-induced H3R26 citrullination and ERα recruitment at target gene promoters. Collectively, our data suggest that E2 stimulation induces the recruitment of PAD2 to target promoters by ERα, whereby PAD2 then citrullinates H3R26, which leads to local chromatin decondensation and transcriptional activation.
authors.affiliation: Baker Institute for Animal Health, College of Veterinary Medicine, Cornell University, Ithaca, NY 14853, USA.
authors.forename: Xuesen
authors.initials: X
authors.lastname: Zhang
authors.forename: Michael
authors.initials: M
authors.lastname: Bolt
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Guertin
authors.forename: Wei
authors.initials: W
authors.lastname: Chen
authors.forename: Sheng
authors.initials: S
authors.lastname: Zhang
authors.forename: Brian D
authors.initials: BD
authors.lastname: Cherrington
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Slade
authors.forename: Christina J
authors.initials: CJ
authors.lastname: Dreyton
authors.forename: Venkataraman
authors.initials: V
authors.lastname: Subramanian
authors.forename: Kevin L
authors.initials: KL
authors.lastname: Bicker
authors.forename: Paul R
authors.initials: PR
authors.lastname: Thompson
authors.forename: Michael A
authors.initials: MA
authors.lastname: Mancini
authors.forename: John T
authors.initials: JT
authors.lastname: Lis
authors.forename: Scott A
authors.initials: SA
authors.lastname: Coonrod
mesh_terms: D000818:Animals; D001120:Arginine / Q000378:metabolism*; D055162:Biocatalysis / Q000187:drug effects; D045744:Cell Line, Tumor; D002843:Chromatin / Q000378:metabolism; D002956:Citrulline / Q000378:metabolism*; D047628:Estrogen Receptor alpha / Q000378:metabolism*; D004967:Estrogens / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D015894:Genome, Human / Q000235:genetics; D006657:Histones / Q000378:metabolism*; D006801:Humans; D006867:Hydrolases / Q000378:metabolism*; D051379:Mice; D059372:Nucleotide Motifs / Q000235:genetics; D011401:Promoter Regions, Genetic / Q000235:genetics; D000080064:Protein-Arginine Deiminase Type 2; D000076342:Protein-Arginine Deiminases; D020218:Response Elements / Q000235:genetics; D014158:Transcription, Genetic / Q000187:drug effects; D015533:Transcriptional Activation / Q000187:drug effects
chemical_list: D002843:Chromatin; C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; D004967:Estrogens; D006657:Histones; D002956:Citrulline; D001120:Arginine; D006867:Hydrolases; C000620352:PADI2 protein, human; D000080064:Protein-Arginine Deiminase Type 2; D000076342:Protein-Arginine Deiminases