Genome-wide profiling of DNA methylation and gene expression identifies candidate genes for human diabetic neuropathy
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RESEARCH
Open Access
Genome-wide profiling of DNA methylation and gene expression identifies candidate genes for human diabetic neuropathy Kai Guo1†, Stephanie A. Eid2†, Sarah E. Elzinga2†, Crystal Pacut2, Eva L. Feldman2 and Junguk Hur1*
Abstract Background: Diabetic peripheral neuropathy (DPN) is the most common complication of type 2 diabetes (T2D). Although the cellular and molecular mechanisms of DPN are poorly understood, we and others have shown that altered gene expression and DNA methylation are implicated in disease pathogenesis. However, how DNA methylation might functionally impact gene expression and contribute to nerve damage remains unclear. Here, we analyzed genome-wide transcriptomic and methylomic profiles of sural nerves from T2D patients with DPN. Results: Unbiased clustering of transcriptomics data separated samples into groups, which correlated with HbA1c levels. Accordingly, we found 998 differentially expressed genes (DEGs) and 929 differentially methylated genes (DMGs) between the groups with the highest and lowest HbA1c levels. Functional enrichment analysis revealed that DEGs and DMGs were enriched for pathways known to play a role in DPN, including those related to the immune system, extracellular matrix (ECM), and axon guidance. To understand the interaction between the transcriptome and methylome in DPN, we performed an integrated analysis of the overlapping genes between DEGs and DMGs. Integrated functional and network analysis identified genes and pathways modulating functions such as immune response, ECM regulation, and PI3K-Akt signaling. Conclusion: These results suggest for the first time that DNA methylation is a mechanism regulating gene expression in DPN. Overall, DPN patients with high HbA1c have distinct alterations in sural nerve DNA methylome and transcriptome, suggesting that optimal glycemic control in DPN patients is an important factor in maintaining epigenetic homeostasis and nerve function. Keywords: Type 2 diabetes, Diabetic peripheral neuropathy, Transcriptomics, Epigenetics, DNA methylation, Gene expression, HbA1c, Human
* Correspondence: [email protected] † Kai Guo, Stephanie A. Eid and Sarah E. Elzinga contributed equally to this work. 1 Department of Biomedical Sciences, School of Medicine and Health Sciences, University of North Dakota, 1301 North Columbia Rd. Stop 9037, Grand Forks, ND 58202-9037, USA Full list of author information is available at the end of the article © The Author(s). 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the
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