Targeted H3R26 deimination specifically facilitates estrogen receptor binding by modifying nucleosome structure

Transcription factor binding to DNA in vivo causes the recruitment of chromatin modifiers that can cause changes in chromatin structure, including the modification of histone tails. We previously showed that estrogen receptor (ER) target gene activation is facilitated by peptidylarginine deiminase 2 (PAD2)-catalyzed histone H3R26 deimination (H3R26Cit). Here we report that the genomic distributions of ER and H3R26Cit in breast cancer cells are strikingly coincident, linearly correlated, and observed as early as 2 minutes following estradiol treatment. The H3R26Cit profile is unlike that of previously described histone modifications and is characterized by sharp, narrow peaks. Paired-end MNase ChIP-seq indicates that the charge-neutral H3R26Cit modification facilitates ER binding to DNA by altering the fine structure of the nucleosome. Clinically, we find that PAD2 and H3R26Cit levels correlate with ER expression in breast tumors and that high PAD2 expression is associated with increased survival in ER+ breast cancer patients. These findings provide insight into how transcription factors gain access to nucleosomal DNA and implicate PAD2 as a novel therapeutic target for ER+ breast cancer.
Author Summary Transcription factors bind to DNA to activate and repress gene transcription. Many transcription factors, particularly nuclear receptors, associate with their cognate DNA element in a highly dynamic manner in vivo. Highly acetylated histone tails and DNase sensitive chromatin are amenable to the initial binding of transcription factors. Upon binding to DNA, transcription factor binding recruits remodelers and coactivators that can cause a concomitant increase in accessibility and acetylation. Herein, we show that estrogen receptor recruitment of a histone deiminase causes the positively charged H3R26 residue to be neutralized. This modification changes the fine structure of the nucleosome particle and facilitates estrogen receptor binding. Lastly, we find that high deiminase expression is associated with increased survival in estrogen receptor-positive breast cancer patients.