Identification of aberrant gene expression associated with aberrant promoter methylation in primordial germ cells between E13 and E16 rat F3 generation vinclozolin lineage.

Y-H Taguchi

doi:10.1186/1471-2105-16-s18-s16

Abstract

BackgroundTransgenerational epigenetics (TGE) are currently considered important in disease, but the mechanisms involved are not yet fully understood. TGE abnormalities expected to cause disease are likely to be initiated during development and to be mediated by aberrant gene expression associated with aberrant promoter methylation that is heritable between generations. However, because methylation is removed and then re-established during development, it is not easy to identify promoter methylation abnormalities by comparing normal lineages with those expected to exhibit TGE abnormalities.MethodsThis study applied the recently proposed principal component analysis (PCA)-based unsupervised feature extraction to previously reported and publically available gene expression/promoter methylation profiles of rat primordial germ cells, between E13 and E16 of the F3 generation vinclozolin lineage that are expected to exhibit TGE abnormalities, to identify multiple genes that exhibited aberrant gene expression/promoter methylation during development.ResultsThe biological feasibility of the identified genes were tested via enrichment analyses of various biological concepts including pathway analysis, gene ontology terms and protein-protein interactions. All validations suggested superiority of the proposed method over three conventional and popular supervised methods that employed t test, limma and significance analysis of microarrays, respectively. The identified genes were globally related to tumors, the prostate, kidney, testis and the immune system and were previously reported to be related to various diseases caused by TGE.ConclusionsAmong the genes reported by PCA-based unsupervised feature extraction, we propose that chemokine signaling pathways and leucine rich repeat proteins are key factors that initiate transgenerational epigenetic-mediated diseases, because multiple genes included in these two categories were identified in this study.

Highlights

Transgenerational epigenetics (TGE) are currently considered important in disease, but the mechanisms involved are not yet fully understood
Gene selection using principal component analysis (PCA)-based unsupervised feature extraction (FE) Figure 1 illustrates the strategy to identify aberrant gene expression associated with aberrant promoter methylation between controls and vinclozolin treated samples during development from E13 to E16
We found that only three genes (IL15, PGAM2, and ZFP36L1) that were not included in the 179 RefSeq mRNAs identified by PCA-based unsupervised FE when N’ = 2000

Summary

Introduction

Transgenerational epigenetics (TGE) are currently considered important in disease, but the mechanisms involved are not yet fully understood. TGE abnormalities expected to cause disease are likely to be initiated during development and to be mediated by aberrant gene expression associated with aberrant promoter methylation that is heritable between generations. TGE mechanisms is that epigenetic markers such as promoter methylation are heritable, and vary over time during development in the generation associated with TGE. Abnormalities caused by TGE must be related to the aberrant timing of promoter methylation/demethylation when compared with normal organisms. Skinner et al [6] recently tried to identify aberrant gene expression associated with aberrant promoter methylation between E13 and E16 germ line in F3 generation vinclozolin lineages, where vinclozolin functions as an endocrine disruptor. Our understanding of the mechanisms by which TGE occurs remains poor

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