Transcriptional networks and epigenomic mechanisms driving lineage-determination of human mesenchymal stem cells

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Susanne Mandrup - Professor, Director at Center for Functional Genomics and Tissue Plasticity (ATLAS) and Department of Biochemistry and Molecular Biology University of Southern Denmark

Photo: University of Southern Denmark

About the lecture

Mesenchymal (stromal) stem cells (MSCs) constitute populations of mesodermal multipotent cells involved in tissue regeneration and homeostasis in many different organs. Defective differentiation and functions of MSCs contribute to age-related changes and diseases, including obesity, sarcopenia, and osteopenia. Furthermore, the plasticity and pleiotropic functions of these cells, make them relevant targets for stem cell-based regenerative therapies. We have characterized the transcriptional and epigenomic changes associated with osteoblast and adipocyte differentiation of human bone marrow-derived MSCs. Our results demonstrate that adipogenesis is driven by considerable remodeling of the chromatin landscape and de novo activation of enhancers, while osteogenesis involves activation of pre-established enhancers. Using machine-learning algorithms for in silico modeling of transcriptional regulation we identified a large and diverse transcriptional network of pro-osteogenic and anti-adipogenic transcription factors. Intriguingly, binding motifs of these factors overlap with single-nucleotide polymorphisms (SNPs) related to bone and fat formation in humans, and knockdown of single members of this network is sufficient to modulate differentiation in both directions, indicating that lineage-determination is a delicate balance between activities of many different transcription factors. To determine how adipogenic enhancers act in 3D space to drive the dramatic remodeling of chromatin during adipocyte differentiation, we applied capture Hi-C and integrated data with genome-wide mapping of transcription factors and enhancer activity. We show that highly connected enhancers drive and coordinate cell type-specific gene programs through the formation of insulated chromatin regions, inside which, enhancers converge on adipogenic gene promoters.

About the speaker

Susanne Mandrup is Professor at Department of Biochemistry and Molecular Biology, University of Southern Denmark, Director of Center of Excellence in Functional Genomics and Tissue Plasticity (ATLAS) and the of the newly established Center for Adipocyte Signaling, Head of the Functional Genomics & Metabolism Research Unit and Chair of Biochemistry and Molecular Biology, Danish Institute of Advanced Study (D-IAS). She obtained her PhD in Biochemistry from University of Southern Denmark (former Odense University) in 1992 and worked among others as a postdoc in Prof. M. Daniel Lane’s group, Department of Biological Chemistry, Johns Hopkins University, Baltimore 1995-96. She was recruited back to Odense as Assistant Professor in 1996 and has since 2008 been full professor.

The Mandrup Group has contributed significantly to the genome-wide understanding of the cross-talk between transcriptional regulation and metabolism, in particular as pertains to the transcriptional regulation of adipocyte differentiation and function. The current focus of the group is to understand the in vivo plasticity of cells in the adipose tissue and the endocrine pancreas, and to understand the basic mechanisms of transcriptional enhancers. The group combines sequencing-based functional-genomics approaches with detailed molecular analyses to study these processes in mouse models, human biopsies and cell cultures.

Susanne Mandrup is elected member of the Royal Danish Academy of Sciences and Letters, Academia Europaea, AcademiaNet, and European Molecular Biology Organization (EMBO), and Knight of the Order of Dannebrog.

 

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Published Oct. 23, 2019 12:33 PM - Last modified Oct. 23, 2019 12:44 PM