title: Coexpression of nuclear receptors and histone methylation modifying genes in the testis: implications for endocrine disruptor modes of action.
abstract: BACKGROUND
  Endocrine disruptor chemicals elicit adverse health effects by perturbing nuclear receptor signalling systems. It has been speculated that these compounds may also perturb epigenetic mechanisms and thus contribute to the early origin of adult onset disease. We hypothesised that histone methylation may be a component of the epigenome that is susceptible to perturbation. We used coexpression analysis of publicly available data to investigate the combinatorial actions of nuclear receptors and genes involved in histone methylation in normal testis and when faced with endocrine disruptor compounds.
  
  
  RESULTS
  The expression patterns of a set of genes were profiled across testis tissue in human, rat and mouse, plus control and exposed samples from four toxicity experiments in the rat. Our results indicate that histone methylation events are a more general component of nuclear receptor mediated transcriptional regulation in the testis than previously appreciated. Coexpression patterns support the role of a gatekeeper mechanism involving the histone methylation modifiers Kdm1, Prdm2, and Ehmt1 and indicate that this mechanism is a common determinant of transcriptional integrity for genes critical to diverse physiological endpoints relevant to endocrine disruption. Coexpression patterns following exposure to vinclozolin and dibutyl phthalate suggest that coactivity of the demethylase Kdm1 in particular warrants further investigation in relation to endocrine disruptor mode of action.
  
  
  CONCLUSIONS
  This study provides proof of concept that a bioinformatics approach that profiles genes related to a specific hypothesis across multiple biological settings can provide powerful insight into coregulatory activity that would be difficult to discern at an individual experiment level or by traditional differential expression analysis methods.
authors.affiliation: Computer Science and Software Engineering, University of Western Australia, Perth, Australia. alisona@ichr.uwa.edu.au
authors.forename: Alison M
authors.initials: AM
authors.lastname: Anderson
authors.forename: Kim W
authors.initials: KW
authors.lastname: Carter
authors.forename: Denise
authors.initials: D
authors.lastname: Anderson
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Wise
mesh_terms: D000328:Adult; D000726:Androgen Antagonists / Q000494:pharmacology; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D019295:Computational Biology; D019175:DNA Methylation / Q000187:drug effects*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D003993:Dibutyl Phthalate / Q000494:pharmacology; D052244:Endocrine Disruptors / Q000494:pharmacology*; D044127:Epigenesis, Genetic / Q000187:drug effects; D020869:Gene Expression Profiling; D056466:Histone Demethylases / Q000235:genetics / Q000378:metabolism*; D011495:Histone-Lysine N-Methyltransferase / Q000235:genetics / Q000378:metabolism*; D006657:Histones / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008297:Male; D051379:Mice; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D010080:Oxazoles / Q000494:pharmacology; D010968:Plasticizers / Q000494:pharmacology; D051381:Rats; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism*; D013737:Testis / Q000166:cytology / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
chemical_list: D000726:Androgen Antagonists; D015415:Biomarkers; D004268:DNA-Binding Proteins; D052244:Endocrine Disruptors; D006657:Histones; D009687:Nuclear Proteins; D010080:Oxazoles; D010968:Plasticizers; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; D003993:Dibutyl Phthalate; D056466:Histone Demethylases; C495195:KDM1A protein, human; C455847:EHMT1 protein, human; D011495:Histone-Lysine N-Methyltransferase; C093563:PRDM2 protein, human; C025643:vinclozolin