Multi-tissue DNA methylation microarray signature is predictive of gene function

Epigenetics. 2022 Nov;17(11):1404-1418. doi: 10.1080/15592294.2022.2036411. Epub 2022 Feb 13.


Background Transcriptional correlation networks derived from publicly available gene expression microarrays have been previously shown to be predictive of known gene functions, but less is known about the predictive capacity of correlated DNA methylation at CpG sites. Guilt-by-association co-expression methods can adapted for use with DNA methylation when a representative methylation value is created for each gene. We examine how methylation compares to expression in predicting Gene Ontology terms using both co-methylation and traditional machine learning approaches across different types of representative methylation values per gene. Methods We perform guilt-by-association gene function prediction with a suite of models called Methylation Array Network Analysis, using a network of correlated methylation values derived from over 24,000 samples. In generating the correlation matrix, the performance of different methods of collapsing probe-level data effect on the resulting gene function predictions was compared, along with the use of different regions surrounding the gene of interest. Results Using mean comethylation of a given gene to its annotated term had an overall highest prediction macro-AUC of 0.60 using mean gene body methylation, across all Gene Ontology terms. This was increased using the logistic regression approach with the highest macro-AUC of 0.82 using mean gene body methylation, compared to the naive predictor of 0.72. Conclusion Genes correlated in their methylation state are functionally related. Genes clustered in co-methylation space were enriched for chromatin state, PRC2, immune response, and development-related terms.

Keywords: DNA methylation; epigenetics; gene function prediction.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Chromatin
  • CpG Islands
  • DNA Methylation*
  • Gene Regulatory Networks*
  • Phenotype


  • Chromatin