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Regulatory Genomics: From Basic Biology to Disease Mechanisms and Ageing

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Genome-wide association studies have uncovered thousands of correlations between genetic variants and complex human diseases. Unfortunately, the majority of these disease-associated variants lie in the non-coding part of the genome, which makes is very difficult to understand the underlying molecular mechanisms. Therefore, to gain a mechanistic understanding of complex genetic diseases and potentially identify molecular intervention points, it is essential to understand how genetic and / or epigenetic variants affect gene regulation. Dr Zaugg will present her and her group recent work that aims at understanding the impact of variation in regulatory elements on complex phenotypes. In particular, she will describe their multi-omics approach to assess transcription factor (TFs) activity based on epigenetics data, build disease-specific TF-target gene regulatory networks, and how we can use these regulatory interactions to gain insights into molecular mechanisms of disease (e.g. pulmonary arterial hypertension (PAH)) and ageing (e.g. of the immune system). In PAH they found extensive remodeling of the active endothelial enhancers in patients that seemed to prime to cells to an aberrant response to endogenous growth factor signaling. For the aging of the immune system our multiomics profiling revealed specific chromatin-related processes downregulated with age that seem to skew the differentiation potential of the cells depending on the age of the donor. Overall, their integrative computational tools with a focus on gene regulation provide a powerful approach to gain mechanistic insights into complex biological processes.

This talk is part of the Seminars on Quantitative Biology @ CRUK Cambridge Institute series.

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