title: Genome-wide analysis reveals PADI4 cooperates with Elk-1 to activate c-Fos expression in breast cancer cells.
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.
authors.affiliation: Baker Institute for Animal Health, College of Veterinary Medicine, Cornell University, Ithaca, New York, USA.
authors.forename: Xuesen
authors.initials: X
authors.lastname: Zhang
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Gamble
authors.forename: Sonja
authors.initials: S
authors.lastname: Stadler
authors.forename: Brian D
authors.initials: BD
authors.lastname: Cherrington
authors.forename: Corey P
authors.initials: CP
authors.lastname: Causey
authors.forename: Paul R
authors.initials: PR
authors.lastname: Thompson
authors.forename: Mark S
authors.initials: MS
authors.lastname: Roberson
authors.forename: W Lee
authors.initials: WL
authors.lastname: Kraus
authors.forename: Scott A
authors.initials: SA
authors.lastname: Coonrod
mesh_terms: D001665:Binding Sites; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D005260:Female; D015894:Genome, Human; D055106:Genome-Wide Association Study; D006801:Humans; D006867:Hydrolases / Q000235:genetics*; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D000080002:Protein-Arginine Deiminase Type 4; D000076342:Protein-Arginine Deiminases; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics* / Q000378:metabolism; D015533:Transcriptional Activation / Q000235:genetics; D050807:ets-Domain Protein Elk-1 / Q000235:genetics* / Q000378:metabolism
chemical_list: D016760:Proto-Oncogene Proteins c-fos; D050807:ets-Domain Protein Elk-1; D006867:Hydrolases; C000629235:PADI4 protein, human; D000080002:Protein-Arginine Deiminase Type 4; D000076342:Protein-Arginine Deiminases