The role of DNA methylation in the regulation of depot-specific gene expression in human adipose tissue

Thesis

Adipose tissue is not homogenous as individual fat depots display regional variation in their physiological properties. It follows that body fat distribution is increasingly being recognised as a major determinant of metabolic disease risk. At the cellular level, depot-specific properties are exhibited by adipocyte precursors during in vitro culture and persist for many generations, suggesting these cells retain an ‘intrinsic memory’ of their anatomical origin which is epigenetic in nature. A primary aim was to identify depot-specific genes whose expression may be regulated by DNA methylation in adipose precursors.

Using two paired preadipocyte cell lines derived from human subcutaneous abdominal and gluteal adipose tissue - to represent upper and lower body fat with their opposing associations with cardiovascular disease and diabetes respectively - depot-specific gene expression and DNA methylation profiles were detected. Furthermore, the expression of certain genes in preadipocytes was found to change in response to treatment with the DNA demethylating agent 5-azacytidine, which suggests DNA methylation may regulate depot-specific gene expression. A secondary aim was to investigate whether glucocorticoids – which are important determinants of body fat distribution – exert their effects through DNA methylation. The synthetic glucocorticoid dexamethasone was found to modulate the expression of some of the differentially expressed genes in preadipocytes, with this effect possibly being mediated by DNA methylation. It has been postulated that depot-specific phenotypes in adipose tissue may arise from developmental differences. Several genes were found to be expressed in a depot-specific fashion during a differentiation time course, suggesting regional variation in adipogenesis may contribute to the generation of depot-specific phenotypes.

Overall, the data presented suggests regional variation within subcutaneous white adipose tissue exists and supports the notion that DNA methylation patterns can, in part, determine adipose tissue heterogeneity.

Authors: Denton, NF

• Publication date: 2013
• DOI: 10.5287/ora-nz60n9y4n
• Type of award: MSc by Research
• Level of award: Masters
• Awarding institution: University of Oxford
• Language: English
• Keywords: epigenetics; glucocorticoids; 5-azacytidine; Adipose; DNA methylation
• Subjects: Biology (medical sciences)