Genome-Wide analysis reveals PADI4 cooperates with Elk-1 to activate C-Fos expression in breast cancer cells

Xuesen Zhang, Matthew J. Gamble, Sonja Stadler, Brian D. Cherrington, Corey P. Causey, Paul R. Thompson, Mark S. Roberson, W. Lee Kraus, Scott A. Coonrod

Research output: Contribution to journalArticle

59 Scopus citations

Abstract

Peptidylarginine deiminase IV (PADI4) catalyzes the conversion of positively charged arginine and methylarginine residues to neutrally charged citrulline, and this activity has been linked to the repression of a limited number of target genes. To broaden our knowledge of the regulatory potential of PADI4, we utilized chromatin immunoprecipitation coupled with promoter tiling array (ChIP-chip) analysis to more comprehensively investigate the range of PADI4 target genes across the genome in MCF-7 breast cancer cells. Results showed that PADI4 is enriched in gene promoter regions near transcription start sites (TSSs); and, surprisingly, this pattern of binding is primarily associated with actively transcribed genes. Computational analysis found potential binding sites for Elk-1, a member of the ETS oncogene family, to be highly enriched around PADI4 binding sites; and coimmunoprecipitation analysis then confirmed that Elk-1 physically associates with PADI4. To better understand how PADI4 may facilitate gene transactivation, we then show that PADI4 interacts with Elk-1 at the c-Fos promoter and that, following Epidermal Growth Factor (EGF) stimulation, PADI4 catalytic activity facilitates Elk-1 phosphorylation, histone H4 acetylation, and c-Fos transcriptional activation. These results define a novel role for PADI4 as a transcription factor co-activator.

Original languageEnglish (US)
Article numbere1002112
JournalPLoS genetics
Volume7
Issue number6
DOIs
StatePublished - Jun 2011

ASJC Scopus subject areas

  • Ecology, Evolution, Behavior and Systematics
  • Molecular Biology
  • Genetics
  • Genetics(clinical)
  • Cancer Research

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    Zhang, X., Gamble, M. J., Stadler, S., Cherrington, B. D., Causey, C. P., Thompson, P. R., Roberson, M. S., Kraus, W. L., & Coonrod, S. A. (2011). Genome-Wide analysis reveals PADI4 cooperates with Elk-1 to activate C-Fos expression in breast cancer cells. PLoS genetics, 7(6), [e1002112]. https://doi.org/10.1371/journal.pgen.1002112