Differential methylation of microRNA encoding genes may contribute to high myopia

Joanna Swierkowska; Sangeetha Vishweswaraiah; Malgorzata Mrugacz; Uppala Radhakrishna; Marzena Gajecka

doi:10.3389/fgene.2022.1089784

Differential methylation of microRNA encoding genes may contribute to high myopia

Front Genet. 2023 Jan 4:13:1089784. doi: 10.3389/fgene.2022.1089784. eCollection 2022.

Authors

Joanna Swierkowska¹, Sangeetha Vishweswaraiah², Malgorzata Mrugacz³, Uppala Radhakrishna², Marzena Gajecka^{1

4}

Affiliations

¹ Institute of Human Genetics, Polish Academy of Sciences, Poznan, Poland.
² Department of Obstetrics and Gynecology, Oakland University William Beaumont School of Medicine, Royal Oak, MI, United States.
³ Department of Ophthalmology and Eye Rehabilitation, Medical University of Bialystok, Bialystok, Poland.
⁴ Chair and Department of Genetics and Pharmaceutical Microbiology, Poznan University of Medical Sciences, Poznan, Poland.

Abstract

Introduction: High myopia (HM), an eye disorder with a refractive error ≤-6.0 diopters, has multifactorial etiology with environmental and genetic factors involved. Recent studies confirm the impact of alterations in DNA methylation and microRNAs (miRNAs) on myopia. Here, we studied the combined aspects evaluating to the role of methylation of miRNA encoding genes in HM. Materials and Methods: From the genome-wide DNA methylation data of 18 Polish children with HM and 18 matched controls, we retrieved differentially methylated CG dinucleotides localized in miRNA encoding genes. Putative target genes of the highest-ranked miRNAs were obtained from the miRDB and included in overrepresentation analyses in the ConsensusPathDB. Expression of target genes was assessed using the RNA sequencing data of retinal ARPE-19 cell line. Results: We identified differential methylation of CG dinucleotides in promoter regions of MIR3621, MIR34C, MIR423 (increased methylation level), and MIR1178, MIRLET7A2, MIR885, MIR548I3, MIR6854, MIR675, MIRLET7C, MIR99A (decreased methylation level) genes. Several targets of these miRNAs, e.g. GNAS, TRAM1, CTNNB1, EIF4B, TENM3 and RUNX were previously associated with myopia/HM/refractive error in Europeans in genome-wide association studies. Overrepresentation analyses of miRNAs' targets revealed enrichment in pathways/processes related to eye structure/function, such as axon guidance, transcription, focal adhesion, and signaling pathways of TGF-β, insulin, MAPK and EGF-EGFR. Conclusion: Differential methylation of indicated miRNA encoding genes might influence their expression and contribute to HM pathogenesis via disrupted regulation of transcription of miRNAs' target genes. Methylation of genes encoding miRNAs may be a new direction in research on both the mechanisms determining HM and non-invasive indicators in diagnostics.

Keywords: DNA methylation; childhood myopia; early-onset high myopia; epigenetic changes; miRNA encoding genes; microRNA target genes.