Title

Peptidylarginine deiminase 2-catalyzed histone H3 arginine 26 citrullination facilitates estrogen receptor alpha target gene activation.

UMMS Affiliation

Department of Biochemistry and Molecular Pharmacology

Date

8-14-2012

Document Type

Article

Medical Subject Headings

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

Disciplines

Biochemistry | Enzymes and Coenzymes | Medicinal-Pharmaceutical Chemistry | Therapeutics

Abstract

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.

Rights and Permissions

Citation: 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

Comments

At the time of publication, Paul Thompson was not yet affiliated with UMass Medical School.

Related Resources

Link to Article in PubMed