Peptidylarginine deiminase 2-catalyzed histone H3 arginine 26 citrullination facilitates estrogen receptor alpha target gene activation.
Department of Biochemistry and Molecular Pharmacology
Animals; Arginine; *Biocatalysis; Cell Line, Tumor; Chromatin; Citrulline; Estrogen Receptor alpha; Estrogens; Gene Expression Regulation, Neoplastic; Genome, Human; Histones; Humans; Hydrolases; Mice; Nucleotide Motifs; Promoter Regions, Genetic; Response Elements; Transcription, Genetic; *Transcriptional Activation
Biochemistry | Enzymes and Coenzymes | Medicinal-Pharmaceutical Chemistry | Therapeutics
Cofactors for estrogen receptor alpha (ERalpha) can modulate gene activity by posttranslationally modifying histone tails at target promoters. Here, we found that stimulation of ERalpha-positive cells with 17beta-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 ERalpha 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 ERalpha after E2 stimulation and that inhibition of either PAD2 or ERalpha strongly suppresses E2-induced H3R26 citrullination and ERalpha recruitment at target gene promoters. Collectively, our data suggest that E2 stimulation induces the recruitment of PAD2 to target promoters by ERalpha, whereby PAD2 then citrullinates H3R26, which leads to local chromatin decondensation and transcriptional activation.
DOI of Published Version
Proc Natl Acad Sci U S A. 2012 Aug 14;109(33):13331-6. doi: 10.1073/pnas.1203280109 Link to article on publisher's site
Proceedings of the National Academy of Sciences of the United States of America
Zhang, Xuesen; Bolt, Michael; Guertin, Michael J.; Chen, Wei; Zhang, Sheng; Cherrington, Brian D.; Slade, Daniel J.; Dreyton, Christina J.; Subramanian, Venkataraman; Bicker, Kevin L.; Thompson, Paul R.; Mancini, Michael A.; Lis, John T.; and Coonrod, Scott A., "Peptidylarginine deiminase 2-catalyzed histone H3 arginine 26 citrullination facilitates estrogen receptor alpha target gene activation." (2012). Thompson Lab Publications. 33.