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Doctoral defence of Suresh Raju, MSc, 22 June 2022: Understanding the TCF7L2 binding site polymorphisms in the context of type 2 diabetes

The doctoral dissertation in the field of Molecular Biology will be examined at the Faculty of Health Sciences at the Kuopio Campus. The public examination will be streamed online.

What is the topic of your doctoral research? Why is it important to study the topic?

The topic of my research is "Understanding the Functional Significance of TCF7L2 Binding Site Polymorphisms to Target Gene Regulation in the Context of Type 2 Diabetes". T-cell factor 7-like 2 (TCF7L2) is a DNA-binding transcription factor that regulates metabolic genes and pathways, and its gene carries genetic variants associated with the risk of type 2 diabetes. In this study a newly developed method was used to identify candidate genetic variants that may affect the gene regulatory function of TCF7L2. This work also characterized the functional role TCF7L2 in gene regulation in a cell culture model of hepatocytes.

What are the key findings or observations of your doctoral research?

Our results for the test case of TCF7L2 provided a basis for screening how potentially clinically relevant human genetic variation for a predicted allelic would influence TCF7L2 binding, and yielded potential rSNPs candidates for TCF7L2, including some that have been associated with metabolically important traits such as obesity or circulating triglyceride levels, or BMI values, or brain-related traits like psychosis or schizophrenia. Our developed method has characterized the sequence dependent TCF7L2 binding on the genomic loci and the effects of rSNPs that may be the developmental cause of important diseases. With respect to how TCF7L2 regulates the activities of hepatocytes, our study has delivered important insights into its target genes and the mechanisms through which TCF7L2 acts in hepatocytes. These findings have improved our understanding of the functional regulation of TCF7L2 of important cellular metabolic pathways. Clarifying the mechanistic role of TCF7L2 gene is very important in elucidating the functional role of this gene in liver cell growth and thus in the development of cancer and/or hepatic metabolic disorders. We also revealed the diverse role of TCF7L2 in hepatocytes. TCF7L2 regulates multiple pathways by either exerting direct and indirect influences in the regulation of target genes.

How can the results of your doctoral research be utilised in practice?

Our developed method is cost effective and easy to customize, and can therefore be applied to any transcription factor, as long as the TF protein can be produced in-vitro and there is at least some a priori information on the consensus binding sequence. The same experimental set-up can be applied for other genes in order to understand the mechanistic role of that particular gene in regulating cellular and metabolic pathways.

What are the key research methods and materials used in your doctoral research?

We conducted various methods in our studies. We developed a microarray based method called Microdot-ELISA to characterize the binding pattern of TCF7L2 in the human genome. To characterize the functional significance of TCF7L2 in cultured hepatocytes, various molecular biological methods including western blotting, RT-PCR, mammalian cell culture, and NGS (RNA-sequencing, ChIP-sequencing, ATAC-sequencing) has been conducted.

The doctoral dissertation of Suresh Raju, Master of Science, entitled Understanding the Functional Significance of TCF7L2 Binding Site Polymorphisms to Target Gene Regulation in the Context of Type 2 Diabetes will be examined at the Faculty of Health Sciences. The Opponent in the public examination will be Docent Kimmo Palin of the University of Helsinki, and the Custos will be Docent Sami Heikkinen of the University of Eastern Finland. The public examination will be held in English.

Doctoral defence online

Photo available for download

Dissertation online (link available later)

For further information, please contact:

Suresh Raju, MSc, suresh.raju (a) uef.fi, tel. +358406356874