Abstract: SA-PO417
Methyl-CG Erosion Define Core Pathways in the Progression of Diabetic Nephropathy
Session Information
- Genetic Diseases of the Kidney - III
November 09, 2019 | Location: Exhibit Hall, Walter E. Washington Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Genetic Diseases of the Kidneys
- 1002 Genetic Diseases of the Kidneys: Non-Cystic
Author
- El-Osta, Assam, Central Clinical School, Monash University, Melbourne, Australia
Background
To apply systems level understanding of the role of DNA methylation, it is important to distinguish the essential sequence elements involved in regulating gene expression. This becomes a particularly challenging task for diabetic kidney disease (DKD) when reliable epigenetic markers such as DNA methylation are limited. While genome-wide methylation studies are typically performed using BeadChip array technology, this does not provide sufficient coverage to construct an integrated epigenetic regulatory network (ERN) important because diabetic nephropathy is considered a complex polygenic and multifactorial disorder. To address this knowledge gap, we examined DNA methylation using massive parallel sequencing to describe an ERN assessing methylation changes from multi-centre diabetes registries.
Methods
DNA methylation sequencing was used to define an epigenetic regulatory network in the Finnish Diabetic Nephropathy (FinnDiane) discovery cohort. DNA methylation changes were also assessed using independent replication cohorts from Hong Kong and Thailand. Methylation mediated gene regulation using primary human renal and vascular endothelial cells confirm functional methylation-dependent CTCF and Pol2B regulation of gene expression.
Results
Differential methylated regions (DMRs) in leukocytes are associated with DKD progression and integrative methylation analyses reveal 494 differentially methylated genes (DMGs) that intersect with CTCF binding sites (181 genes with increased- and 313 genes with reduced- methylation). Integration of DNA methylation and CTCF/Pol2B profiles confirm the major pathways associated with insulin receptor signalling, lipid metabolism and integrin cell interactions with the progression of DKD.
Conclusion
The progression of nephropathy in T1D remains unexplained, using multi-centre registries combined with functional studies using primary human renal cells we identify methylation indices and specifically erosion on core genes that functionally regulate pathways describing an epigenetic regulatory network.
Funding
- Government Support - Non-U.S.