Targeted H3R26 Deimination Specifically Facilitates Estrogen Receptor Binding by Modifying Nucleosome Structure

Abstract

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.

PAD1 promotes epithelial-mesenchymal transition and metastasis in triple-negative breast cancer cells by regulating MEK1-ERK1/2-MMP2 signaling

“…Several studies from others and us have shown that, in addition to targeting histones [18–20], PAD4 can also regulate to function on non-histone proteins via citrullination [22–26,29]. We therefore wondered whether PAD1 could modulate MEK1 via similar mechanisms.…”

“…Recently, PAD -mediated protein citrullination has gathered increased attention due to its emerging role in various cancers [17]. For example, PAD2 and PAD4 can catalyze citrullination of histone H3 and H4 at gene promoters, leading to local changes in chromatin structure and modulation of tumor-associated gene transcription in human breast cancer cells [18,19]. PAD4 was also found to mediate citrullination of histone H3 at the apoptosis-related gene promoters in other cancer cells [20,21].…”

Chemical Biology of Protein Arginine Modifications in Epigenetic Regulation

“…73 The authors further suggest that histone citrullination might be a critical prognostic for ER+ tumor development and is thus suited to stratify ER+ tumors into clinically relevant subsets. This observation also raises the intriguing question of whether histone citrullination may act as either a tumor promoter or a suppressor mark in a context and or isozyme-dependent manner.…”

Downregulation of the Deiminase PADI2 Is an Early Event in Colorectal Carcinogenesis and Indicates Poor Prognosis

“…However, the outcome of such a coactivator function is strongly dependent on the cellular context. In the estrogen receptor-positive subgroup of breast cancer patients, PADI2 expression correlated with good prognosis and in breast cancer cells was shown to facilitate the binding of the estrogen receptor to its target genes (18).…”