Judith B Zaugg
European Molecular Biology Laboratory
Regulatory Genomics: from Basic Biology to Disease Mechanisms
AbstractGenome-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. Here I will present our recent work that aims at understanding the impact of variation in regulatory elements on complex phenotypes. In particular, I will describe our multi-omics approaches of for gaining structural insights into cooperative transcription factor (TF) binding using genomics data, to assess TFs activity based on epigenetics data and build disease-specific TF-target gene regulatory networks that can be used to gain insights into molecular mechanisms of disease and ageing (e.g. pulmonary arterial hypertension and immune system). In PAH we find extensive remodeling of the active endothelial enhancers in patients that seemed to prime to cells to an aberrant response to endogenous growth factor signaling. Similarly, for the aging of the immune system our multiomics profiling revealed epigenetic processes de-regulated with age that seem to prime stem cells towards a specific cell fate. Overall, our integrative computational tools with a focus on gene regulation provide a powerful approach to gain mechanistic insights into complex biological processes.
Judith Zaugg started her group in Computational and Regulatory Genomics at EMBL in 2014 (www.zaugg.embl.de). Since 2018 she is also co-leading research group on Stem Cell-Niche Networks within the framework of the Molecular Medicine Partnership Unit (MMPU) at the University hospital Heidelberg. She studied chemical and molecular biology at ETH in Zurich, obtained her PhD at Cambridge University and EMBL-EBI, and went to Stanford for her postdoctoral research where she was co-leading studies on epigenetic variation across individuals, and discovered that many so-called epigenetic marks do in fact have a genetic basis (Grubert et al). Her group at EMBL focuses on computational biology in epigenetics and gene regulation, developing computational tools (e.g. differential transcription factor activity diffTF – Berest et al) to understand basic gene regulatory principles (e.g. how CTCF mediated chromatin looping is involved in splicing – Ruiz-Velasco et al) and epigenetic mechanisms underlying complex diseases. Her MMPU group focuses on understanding the interaction between the stem cell populations within the hematopoietic niche, and how aging and blood cancer affect these interactions (e.g. Garg et al).
Berest et al. (2019): Quantification of differential transcription factor activity and multiomic-based classification into activators and repressors: diffTF. BioRxiv doi:10.1101/368498 (Cell Reports in press) https://git.embl.de/grp-zaugg/diffTF
Ruiz-Velasco et al. (2017): CTCF-mediated chromatin loops between promoter and gene body regulate alternative splicing across individuals: Cell Systems 5 (6), 628-637
Garg et al. (2019) Hepatic leukemia factor is a novel leukemic stem cell regulator in DNMT3A, NPM1, and FLT3-ITD triple-mutated AML. Blood. https://doi.org/10.1182/blood.2018862383
Grubert et al. Genetic Control of Chromatin States in Humans Involves Local and Distal Chromosomal Interactions. Cell. 162 (5): 1051-1065
BioSB 2020Registration website for BioSB 2020
BioSB 2020BioSB 20200.00EUROnlineOnly2019-01-01T00:00:00ZTo be announcedTo be announced