Osteogenesis depends on commissioning of a network of stem cell transcription factors that act as repressors of adipogenesis

Alexander Rauch, Anders K. Haakonsson, Jesper G.S. Madsen, Mette Larsen, Isabel Forss, Martin R. Madsen, Elvira L. Van Hauwaert, Christian Wiwie, Naja Z. Jespersen, Michaela Tencerova, Ronni Nielsen, Bjørk D. Larsen, Richard Röttger, Jan Baumbach, Camilla Scheele, Moustapha Kassem, Susanne Mandrup

Research output: Contribution to journalArticlepeer-review

138 Scopus citations

Abstract

Mesenchymal (stromal) stem cells (MSCs) constitute populations of mesodermal multipotent cells involved in tissue regeneration and homeostasis in many different organs. Here we performed comprehensive characterization of the transcriptional and epigenomic changes associated with osteoblast and adipocyte differentiation of human MSCs. We demonstrate that adipogenesis is driven by considerable remodeling of the chromatin landscape and de novo activation of enhancers, whereas osteogenesis involves activation of preestablished enhancers. Using machine learning algorithms for in silico modeling of transcriptional regulation, we identify a large and diverse transcriptional network of pro-osteogenic and antiadipogenic transcription factors. Intriguingly, binding motifs for these factors overlap with 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, thus indicating that lineage determination is a delicate balance between the activities of many different transcription factors.

Original languageEnglish
Pages (from-to)716-727
Number of pages12
JournalNature Genetics
Volume51
Issue number4
DOIs
StatePublished - 1 Apr 2019

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