Genome-wide analysis of the DNA methylation landscapes in human tissues
The prevalence of type 2 diabetes and obesity is rapidly increasing worldwide. Both pancreatic islets and adipose tissue play an important role in metabolic processes in humans, and dysfunction in these tissues may contribute to the pathogenesis of type 2 diabetes and obesity. Epigenetics is thought to be one of the processes by which the environment interacts with cellular phenotypes. However, current knowledge about the role of epigenetics in type 2 diabetes and obesity remains limited. In 4 studies included in this thesis, we have shown that the DNA methylome in pancreatic islets and adipose tissue reflects environmental factors, metabolic phenotypes and type 2 diabetes status.
In study 1 we investigated whether the DNA methylome in human adipose tissue exhibit changes in DNA methylation in response to 6 months exercise intervention. Overall, we identified 17,975 CpG sites significantly altered before versus after the intervention. These alterations imvolve some of the genes previously associated with type 2 diabetes and obesity, including TCF7L2 and KCNQ1.
Next, in study 2 we identified a set of CpG sites which are associated with age, BMI or HbA1c in human adipose tissue. CpG sites associated with age in adipose tissue were annotated to previously known blood-based biomarkers for age, such as ELOVL2. Moreover, we identified multiple genes, including such obesity loci as FTO, ITIH5 and CCL18, where both DNA methylation and mRNA expression significantly correlated with BMI.
In study 3, we investigated the influence of genetic variation on DNA methylation in human adipose tissue and charted a map of SNP-CpG interactions in numan adipose tissue. We identified interactions between some of the SNP´s previously implicated in obesity and lipid biology and the DNA methylome in human adipose tissue. We also demonstrated that DNA methylation can play a mediating role between genetic variation and transcriptional activity.
In study 4, we used whole-genome bisulfite sequencing to chart the DNA methylome of human pancreatic islets, and to identify contiguous genomic regions significantly different between donors with or without type 2 diabetes. We found that in human pancreatic islets differentially methylated regions are asociated with transcriptional activity and are overrepresented in regulatory regions such as enhancers and transcription factor binding sites.
Overall, these studies suggest that DNA methylation plays a role in the way the invironment affects cellular function in both human adipose tissuew and pancreatic islets.