Department of Biochemistry and Molecular Pharmacology
Binding Sites; Breast Neoplasms; Cell Line, Tumor; Female; *Genome, Human; Genome-Wide Association Study; Humans; Hydrolases; Phosphorylation; Promoter Regions, Genetic; Proto-Oncogene Proteins c-fos; Transcriptional Activation; ets-Domain Protein Elk-1
Biochemistry | Enzymes and Coenzymes | Genetics and Genomics | Medicinal-Pharmaceutical Chemistry | Therapeutics
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.
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Copyright: © 2011 Zhang et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
DOI of Published Version
PLoS Genet. 2011 Jun;7(6):e1002112. doi: 10.1371/journal.pgen.1002112. Epub 2011 Jun 2. Link to article on publisher's site
Zhang, Xuesen; Gamble, Matthew J.; Stadler, Sonja; Cherrington, Brian D.; Causey, Corey P.; Thompson, Paul R.; Roberson, Mark S.; Kraus, W Lee; and Coonrod, Scott A., "Genome-wide analysis reveals PADI4 cooperates with Elk-1 to activate c-Fos expression in breast cancer cells." (2011). Thompson Lab Publications. 48.