US EPA

1249813 

Journal Article 

Coexpression of nuclear receptors and histone methylation modifying genes in the testis: implications for endocrine disruptor modes of action 

Anderson, AM; Carter, KW; Anderson, D; Wise, MJ 

2012 

1 

PLoS ONE
EISSN: 1932-6203 

PLoS One. 2012; 7(4):e34158. [PloS one] 

7 

4 

e34158 

English 

22496781 

10.1371/journal.pone.0034158 

WOS:000304855200033 

https://search.proquest.com/docview/1340945236?accountid=171501
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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.

METHODOLOGY/PRINCIPAL FINDINGS: 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/SIGNIFICANCE: 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. 

Sciences: Comprehensive Works; Histones; Chemical disruption; Methylation; DNA methylation; Methyltransferases; Epigenetics; Gene disruption; Transcriptional control; Childrens health; Receptors; Toxicity; Bioinformatics; Bayesian analysis; Combinatorial analysis; Gene regulation; Transcription; Vinclozolin; Biology; Signalling; Signalling systems; Endocrine disruptors; Perturbation methods; Chromatin; Gene expression; Studies; Medical research; Deoxyribonucleic acid--DNA; Ligands; Dibutyl phthalate; Stem cells; Enzymes; Nuclear receptors; Mode of action; Health risks; Perth Western Australia Australia