Abstract
BackgroundDiabetic 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.ResultsUnbiased 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.ConclusionThese 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.
Highlights
Diabetic peripheral neuropathy (DPN) is the most common complication of type 2 diabetes (T2D)
Study population To identify specific mechanisms that are differentially transcribed in T2D and DPN, we determined gene expression profiles using RNA-seq in sural nerve biopsies obtained from DPN patients from a double-blind placebo-controlled clinical trial of a candidate treatment that proved ineffective [28, 29]
Patient clinical characteristics are available in Additional file 2: Table S1, including hemoglobin A1c (HbA1c), triglyceride and cholesterol levels, and neuropathy phenotyping by myelinated fiber density (MFD) counts and O’Brien neuropathy score
Summary
Diabetic peripheral neuropathy (DPN) is the most common complication of type 2 diabetes (T2D). 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. Microvascular complications are more common and affect multiple tissues including the eye, kidney, and nerve [2, 3]. Diabetic neuropathy affects the nerve and is the most prevalent microvascular complication that can present in multiple forms, the most common being diabetic peripheral neuropathy (DPN) [4]. DPN affects up to 60% of T2D patients and is characterized by distal-to-proximal nerve damage that results in reduced sensation, chronic pain, increased infection risk, and recurrent foot ulceration that can lead to lower limb amputations [4,5,6]. Understanding the pathogenesis of DPN is critical for developing mechanismbased therapies
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