PracticeUpdate

DNA Methylation, LXR/RXR Activation, and Multiple Immune Signaling Pathways Likely Play a Role in Diabetic Polyneuropathy These pathways may provide newmechanism-based therapeutic targets

D NA methylation, LXR/RXR activa- tion, and multiple immune signaling pathways have been found to play a possible role in diabetic polyneuropathy. These outcomes from a DNA methylation study and a transcriptional signature study were reported at ICNMD 2018. Eva L. Feldman, MD, PhD, of the University of Michigan in Ann Arbor, Michigan, assessed the DNA methylation profiles of 12 individuals with diabetic peripheral neuropathy. Examination of sural nerve biopsies from these individuals revealed that six of them exhibited significant nerve regeneration, whereas other six displayed significant nerve degeneration over a period of 52 weeks. These samples underwent reduced representation bisulfite sequencing for analysis of DNA methylation between individuals who exhibited sural nerve regeneration and those who exhibited degeneration. A total of 3460 differentially methylated correlations between differentially meth- ylated 5'-C-phosphate-G-3's and 246 differentially methylated regions were revealed between the two cohorts. Analyses of genes associated with the differentially methylated 5'-C-phosphate- G-3's identified pathways highly enriched in neuron development and differentia- tion, as well as pathways associated with cancer. Dr. Feldman explained that, DNA methyl- ation is an important epigenetic regulator in both health and disease. However, no investigations of possible alterations in DNA methylation in the peripheral nerves DNA methylation helps regulate diabetic peripheral neuropathy

These sub-networks were further merged into a single network of 688 genes. Functional analyses of the identified shared networks between murine and human datasets revealed that genes involved in LXR/RXR activation and adipo- genesis were highly affected by diabetes and conserved across both species. Centrality analysis detected the most highly connected genes that may play important roles in this cross-species shared network of diabetic peripheral neuropathy, including PIK3CA, MAPK8, CD44, MAPK1, CREB1, LEP, CCL2, JUN, ESR1, FOS, CD36, IL1B, HGF, and PLAT. These genes indicate enrichment of different pathways. The most significant pathways include glucocorticoid receptor signaling, multiple cytokine pathways, and chemokine signaling. Dr. Feldman explained that diabetic peripheral neuropathy is among the most common complications of diabetes. Despite extensive research, underlying mechanisms leading to diabetic periph- eral neuropathy are not fully understood. Multiple murine models and human sam- ples have been examined, but a unified systematic approach is yet to compare observed changes between groups. Such comparison may help to identify a pos- sible conserved mechanism of diabetic peripheral neuropathy. Dr. Feldman concluded that the systems biology approach identified highly con- served pathways across human and murine models. These pathways include LXR/RXR activation and multiple immune signaling pathways, and likely play a role in the pathogenesis of diabetic periph- eral neuropathy providing possible new mechanism-based targets of therapy. www.practiceupdate.com/c/70786

of individuals with diabetic neuropathy have been performed. Dr. Feldman concluded that DNA methyl- ation plays an important role in regulating nervous system development and cellular proliferation in the progression or regres- sion of diabetic peripheral neuropathy. Additionally, these novel results provide insights into possible epigenetic regula- tion of diabetic peripheral neuropathy and offer useful information for future research in the disorder. Transcriptional signature provides possible new therapeutic targets Dr. Feldman also identified transcriptional pathways related to diabetic peripheral neuropathy that were conserved across human and various murine models of dia- betes using a systems biology approach. She collected eight microarray datasets of peripheral nerve samples from murine models of type 1 (streptozotocin-treated) and type 2 (db/db [diabetic] and ob/ ob [obese]) diabetes at different ages and from humans with non-progressive and progressive diabetic peripheral neuropathy. Dr. Feldman identified differentially expressed genes between control and diabetic samples in murine models. Non- progressive and progressive human samples using a unified analysis pipeline. She constructed a transcriptional network for each differentially expressed gene set based on literature-derived gene-gene interaction information. Dr. Feldman identified shared sub-networks between human and murine networks using a net- work-comparison program. Overall, seven pairwise human-ver- sus-murine comparisons resulted in sub-networks including 46 to 396 genes.

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