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

PLoS Genet. 2014 Sep 11;10(9):e1004613. doi: 10.1371/journal.pgen.1004613. eCollection 2014 Sep.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Breast Neoplasms / genetics
  • Breast Neoplasms / metabolism
  • Breast Neoplasms / mortality
  • Chromatin Assembly and Disassembly
  • Estrogens / metabolism
  • Estrogens / pharmacology
  • Female
  • Gene Expression Profiling
  • Gene Expression Regulation / drug effects
  • Genomics
  • Histones / metabolism*
  • Humans
  • Hydrolases / genetics
  • Hydrolases / metabolism
  • MCF-7 Cells
  • Nucleosomes / metabolism*
  • Prognosis
  • Protein Binding
  • Protein-Arginine Deiminase Type 2
  • Protein-Arginine Deiminases
  • Receptors, Estrogen / metabolism*


  • Estrogens
  • Histones
  • Nucleosomes
  • Receptors, Estrogen
  • Hydrolases
  • PADI2 protein, human
  • Protein-Arginine Deiminase Type 2
  • Protein-Arginine Deiminases

Associated data

  • GEO/GSE58177