Institute of Bioengineering – Laboratory of Systems Biology and Genetics – EPFL
Our main focus is to unravel the metazoan gene regulatory code and to examine how variations in this code affect molecular and organismal diversity. As one of our main model systems, we focus on mesenchymal stem cell function with a specific focus on understanding the transcriptional mechanisms mediating white, beige, and brown fat cell differentiation:
1. Examine the origin, diversity and function of white, brite and brown fat cells using single cell transcriptomics
Using single-cell RNA sequencing (scRNA-seq), we aim to uncover the molecular identity of white, beige and brown fat cell precursors, map their location on adipocyte lineage trees, and determine cellular composition differences between fat depots both unperturbed and after intervention (i.e. exposure to cold to induce browning). Further, we will investigate the contribution of the different adipose cell precursors/populations to development of metabolism associated disorders such as obesity and metabolic syndrome.
2. Study gene regulatory networks mediating determination and terminal differentiation of white, brite and brown fat cells
Although many of the key transcription factors controlling white fat cell differentiation have been characterized, a cohesive model of the underlying molecular events has yet to be revealed. Further, the transcriptional regulation of brite and brown fat cell differentiation is substantially less well understood. Combining differential expression analyses (RNAseq/scRNA-seq), chromatin landscape data (histone modification ChIP-seq), as well as large-scale transcription factor (TF) perturbation screens, we aim to unravel regulatory networks that impact adipogenesis. Primarily, our ambitions in this field are focused on TFs (Gubelmann, Raghav and Schwalie et al., 2014)(Pradhan et al., 2017) and their co-regulators (Raghav and Waszak et al., 2012). Ultimately, we pursue in-vivo validation of the identified factors in mouse models, in collaboration with Christian Wolfrum's lab at ETH Zurich and Martin Klingenspor's lab at TU Munich.
3. Probe the impact of genetic variation on adipogenic differentiation
In parallel to extensive analyses of murine gene regulatory networks underlying adipose cell differentiation and function we are focused on the molecular characterization of human adipogenic precursor populations. As an emerging and very promising source of autologous multipotent adult stem cells, adipose derived human mesenchymal stem cells (ASCs) are increasingly used in diverse biomedical applications. However, the lack of comprehensive molecular characterisation impedes its growing clinical implementation. Using the single cell transcription profiling, we are assessing the cellular heterogeneity of ASCs populations obtained from human lipoaspirate samples to reveal the traits associated with the highest multipotency. Another goal is to address the impact of genetic variation on differentiation capacities of ASCs. These projects are being done in collaboration with the Swiss Stem Cell Foundation (SSCF) in Lugano.
- Adipose biology
- Gene regulatory networks
- Transcription factor
- Fat cell function