Circulating cell-free DNA methylation mirrors alterations in cerebral patterns in epilepsy

Abstract

Abstract Background: DNA methylation profiling of circulating cell-free DNA (cfDNA) has rapidly become a promising strategy for biomarker identification and development. The cell-type-specific nature of DNA methylation patterns and the direct relationship between cfDNA and apoptosis can potentially be used non-invasively to predict local alterations. In addition, direct detection of altered DNA methylation patterns performs well as a biomarker. In a previous study, we demonstrated marked DNA methylation alterations in brain tissue from patients with mesial temporal lobe epilepsy with hippocampal sclerosis (MTLE-HS) patients. Experimental Design: We performed DNA methylation profiling in cfDNA isolated from serum of MTLE patients and healthy controls using beadchip arrays followed by systematic bioinformatic analysis including deconvolution analysis and integration with DNase accessibility datasets. Results: Differential cfDNA methylation analysis showed overrepresentation of gene ontology terms and transcription factors related to central nervous system function and regulation. Deconvolution analysis of the DNA methylation datasets ruled out the possibility that the observed differences were due to changes in the proportional contribution of cortical neurons in cfDNA. Moreover, we found no overrepresentation of neuron- or glia-specific patterns in the described cfDNA methylation patterns. However, the MTLE-HS cfDNA methylation patterns featured significant overrepresentation of the epileptic DNA methylation alterations previously observed in hippocampus. Conclusions: Our results support the use of cfDNA methylation profiling as a rational approach to seeking non-invasive and reproducible epilepsy biomarkers.