Mapping the regulatory networks underlying fat cell differentiation.
We have consistently used adipogenesis as an intuitive model system to increase our understanding of the structural and functional properties of the regulatory networks driving cellular differentiation. For example, using integrative genomics, we generated novel insights into the function of co-repressors (nuclear co-repressor 2 / NCoR2 (Raghav et al., Mol. Cell, 2012); and KAP-1 (Chen et al., Nature Comm., 2019) during adipogenesis. In a separate study, we exploited the generation of a comprehensive mouse TF clone library in our lab (Gubelmann et al., Mol. Syst. Biol., 2013) to conduct a large-scale TF overexpression screen to identify positive regulators of adipogenesis. We found that the top hit, ZEB1, acts as a central regulator of both early and late adipogenesis by capacitating other TFs, possibly through recruitment of the co-regulatory machinery, to mediate transcriptional activation (Gubelmann et al., eLife, 2014). This is in contrast with the classical view of ZEB1 exerting its regulatory role though repression and by competing with E-box-binding transcriptional activators.
Mapping cellular heterogeneity in adipose tissue.
Our work on ZEB1 also triggered our interest in better understanding the cellular origin of adipocytes given the involvement of ZEB1 in mesenchymal stem cell (MSC) function, clarifying our interest in using scRNAseq-based approaches to profile the diversity and organization of MSCs. In a landmark paper, we were the first to profile the heterogeneity of mouse adipose stem and precursor cells (ASPCs) using single cell transcriptomics, revealing several distinct ASPC subpopulations (Schwalie et al., Nature, 2018; Highlighted in several international news outlets (incl. Newsweek, Wired)). We identified one of these as CD142+ adipogenesis-regulatory cells (“Aregs”), showing that Aregs can suppress adipogenesis in a paracrine manner involving, among other pathways, retinoic acid signaling (Zachara et al., EMBO J, 2022).
In a recent paper (Ferrero et al., Cell Metabolism, 2024), we have discovered a functional, cellular homolog of Aregs in human visceral adipose tissue, indicating that adipogenesis-suppressive stromal cells might well be a common feature underlying adipose tissue homeostasis.