Elucidating the mechanistic principles underlying regulatory variation-driven molecular and organismal diversity.
Our work examining the regulatory effects of genomic variation has resulted into the groundbreaking discovery that non-coding variants can drive coordinated regulatory processes such as TF DNA binding and chromatin modifications over regions that span >100 kb (Kilpinen et al., Science, 2013). We termed these molecularly linked regions variable “chromatin modules” (CMs), introducing a pioneering concept that enhances our understanding of how regulatory variation shapes molecular, cellular and even organismal diversity (Waszak et al., Cell, 2015). We have since aimed to provide a mechanistic basis as to how these CMs may form in vivo and to explore their relevance to understand disease (Llimos et al., Nature Comm., 2022). As such, we have recently discovered a new class of TFs: ‘context TFs’ which do not directly initiate gene activity, but are nonetheless crucial in mediating cooperation both locally as well as across regulatory elements, thus supporting CM formation (Kribelbauer et al., Nature Genetics, 2024).
Mapping how regulatory variation contributes to phenotypic diversity.
Human geno-phenotype studies tend to be biased by environmental variation and limited sampling. To address this, we have contributed to a single-cell atlas of Drosophila melanogaster(https://flycellatlas.org/; Li et al., Science, 2022) and to the generation of a nuclear and mitochondrial DNA variant catalog for the Drosophila Genetic Reference Panel (Massouras et al., PLoS Genetics, 2012; Huang et al., Genome Research, 2014; Bevers et al., Nature Metabolism, 2019), which is currently one of the most comprehensive structural variant resources for any natural population. Using this variant catalog, we were able to i) show that mitochondrial genotype influences specific metabolic phenotypes such as food intake (Bevers et al., Nature Metabolism, 2019), ii) uncover remarkable molecular and functional variation in the resistance to enteric infection among fly lines (Bou Sleiman et al., Nature Comm., 2015; Frochaux et al., Genome Biology, 2020), further showing that enteric infection induces a specific splicing program of 5’ intron retention (Bou Sleiman et al., Genome bIology, 2020), and iii) reveal extensive tissue-specific expression variation and novel regulators underlying circadian behavior (Litovchenko et al., Science Advances, 2021).