Whole-genome methylation analysis reveals novel epigenetic perturbations of congenital scoliosis

Abstract

Congenital scoliosis (CS) is a congenital disease caused by malformations of vertebrae. Recent studies demonstrated that DNA modification could contribute to the pathogenesis of disease. This study aims to identify epigenetic perturbations that may contribute to the pathogenesis of CS. Four CS patients with hemivertebra were enrolled and underwent spine correction operations. DNA was extracted from the hemivertebrae and spinal process collected from the specimen during the hemivertebra resection. Genome-wide DNA methylation profiling was examined at base-pair resolution using whole-genome bisulfite sequencing (WGBS). We identified 343 genes with hyper-differentially methylated regions (DMRs) and 222 genes with hypo-DMRs, respectively. These genes were enriched in the mitogen-activated protein kinase (MAPK) signaling pathway, calcium signaling pathway, and axon guidance in Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways and were enriched in positive regulation of cell morphogenesis involved in differentiation, regulation of cell morphogenesis involved in differentiation, and regulation of neuron projection development in Biological Process of Gene Ontology (GO-BP) terms. Hyper-DMR-related genes, including IGHG1, IGHM, IGHG3, RNF213, and GSE1, and hypo DMR-related genes, including SORCS2, COL5A1, GRID1, RGS3, and ROBO2, may contribute to the pathogenesis of hemivertebra. The aberrant DNA methylation may be associated with the formation of hemivertebra and congenital scoliosis.

Retrospective Analysis of Associated Anomalies in 636 Patients with Operatively Treated Congenital Scoliosis

“…Furthermore, epigenetic modifications have been reported to be associated with congenital scoliosis. In a previous study, we enrolled 4 patients with a hemivertebra, and identified differentially methylated regions (DMRs) in the entire genome, and compared the methylation levels of these regions between the hemivertebra body and the spinous process in each patient 30 . As a result, we found 5 genes within these DMRs that were hypermethylated and 5 that were hypomethylated in the hemivertebra bod, and these genes may contribute to the occurrence of a hemivertebra.…”

Global hypomethylation in childhood asthma identified by genome‐wide DNA‐methylation sequencing preferentially affects enhancer regions

“…This study has to be seen in the light of some limitations. The sample size of whole-genome sequencing approaches seems to be low when compared to previous EWAS using less cost-intensive array based epigenetic profiling methods, 5,8,58 however, in comparison to previous WGBS studies [59][60][61][62] we included a considerable higher number of samples. In addition, the enrichment of the DMRs in the asthma pathway, the overlap between the DMRassociated genes with known asthma genes such as IL4, EPX, IL5RA and ZFPM1 as identified by NLP, in conjunction with the overlap of previously reported CpG sites (e.g.…”

Molecular landscape of congenital vertebral malformations: recent discoveries and future directions

“…Recent studies showed that aberrant DNA methylation might be linked with the pathogenesis of CS. As compared with healthy individuals, CS patients showed hypermethylation in KAT6B , TNS3 , IGHG1 , IGHM , IGHG3 , RNF213 , and GSE1 , and hypomethylation in SORCS2 , COL5A1 , GRID1 , RGS3 , and ROBO2 [ 143 – 145 ]. Moreover, DNA methylation is a critical mechanism in the process of genomic imprinting, an epigenetic mode of inheritance in which genes are expressed exclusively from one parental chromosome, depending on their parental origin.…”

“…Simultaneously, integrating genotype, phenotype, and epigenetic factors has been proposed as a promising approach to unraveling the molecular basis of rare diseases [ 153 , 154 ]. So far, only one promising study has explored the global genome-wide methylation profile in CS patients, albeit with a small sample size of n = 4 [ 145 ]. To expand the scope of methylation investigations in CS and initiate studies in other described VMs disorders, novel methods such as comprehensive whole-genome bisulfite sequencing and methylome arrays covering approximately 850,000 loci could be used.…”