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

Cofactors for estrogen receptor alpha (ER alpha) can modulate gene activity by posttranslationally modifying histone tails at target promoters. Here, we found that stimulation of ER alpha-positive cells with 17 beta-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 ER alpha 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 ER alpha after E2 stimulation and that inhibition of either PAD2 or ER alpha strongly suppresses E2-induced H3R26 citrullination and ER alpha recruitment at target gene promoters. Collectively, our data suggest that E2 stimulation induces the recruitment of PAD2 to target promoters by ER alpha, whereby PAD2 then citrullinates H3R26, which leads to local chromatin decondensation and transcriptional activation.