Molecular node

We have contributed to seminal studies demonstrating first examples of translating non-coding genetic signals discovered in genetic epidemiology (GWAS) into mechanistic models at the cellular level (10.1056/NEJMoa1502214, 10.1016/j.cell.2013.10.058). In this project we will use cutting-edge whole-genome approaches to assess changes in methylation status and gene regulation in adipose tissue biopsies and blood samples collected from dietary intervention studies, as well as in human and mouse cell culture models (including primary human adipose cells). These state-of-the-art techniques include ChIP-seq (e.g. for histone methylation marks), RNA-seq (transcriptomics) and ATAC-seq (chromatin accessibility), coupled with functional studies of gene regulation in cell culture. We regard chromatin accessibility as central to the diet-genome interplay, by altering gene expression, cell function and whole-body regulation of energy metabolism. We have particular expertise in transcriptional regulation and functional studies. In ongoing translational projects, we are integrating epigenetic and transcriptomic data to improve the understanding of changes in the transcriptional landscape during white and brown adipocyte differentiation. Together with international collaborators we use new deep-sequencing approaches (ATAC-seq, STARR-seq) to map active cis-regulatory motifs in open chromatin regions, and RNA-seq to identify novel relationships between motifs of interest and the regulated transcripts. Altogether, application of these new techniques will provide mechanistic insight into how altered methylation and cell function may mediate the weight changes observed in epidemiological and clinical studies. SLC7A10 was previously reported as a marker of mature white adipocytes (10.1126/scitranslmed.3008490), and in a recent project we have found that its expression in adipocytes strongly depends on common genetic variants linked to body composition and type 2 diabetes, particularly in visceral fat (revised manuscript submitted). In another recent study we have established 3-hydroxyisobutyrate as a strong marker of insulin resistance in type 2 diabetes and obesity that modulates white and brown adipocyte metabolism (10.2337/db19-1174). Other recent work are included here: 10.1016/j.metabol.2019.154014, 10.1016/j.tem.2019.08.011, 10.1016/j.metabol.2019.153999.