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

Autor: Rauch A; Functional Genomics and Metabolism Research Unit, Department of Biochemistry and Molecular Biology, University of Southern Denmark, Odense, Denmark., Haakonsson AK; Molecular Endocrinology and Stem Cell Research Unit (KMEB), Department of Endocrinology and Metabolism, Odense University Hospital and Department of Clinical Research, University of Southern Denmark, Odense, Denmark., Madsen JGS; Functional Genomics and Metabolism Research Unit, Department of Biochemistry and Molecular Biology, University of Southern Denmark, Odense, Denmark., Larsen M; Functional Genomics and Metabolism Research Unit, Department of Biochemistry and Molecular Biology, University of Southern Denmark, Odense, Denmark., Forss I; Functional Genomics and Metabolism Research Unit, Department of Biochemistry and Molecular Biology, University of Southern Denmark, Odense, Denmark., Madsen MR; Functional Genomics and Metabolism Research Unit, Department of Biochemistry and Molecular Biology, University of Southern Denmark, Odense, Denmark., Van Hauwaert EL; Functional Genomics and Metabolism Research Unit, Department of Biochemistry and Molecular Biology, University of Southern Denmark, Odense, Denmark., Wiwie C; Department of Mathematics and Computer Science, University of Southern Denmark, Odense, Denmark., Jespersen NZ; Centre of Inflammation and Metabolism and Centre for Physical Activity Research, Rigshospitalet, University Hospital of Copenhagen, Copenhagen, Denmark.; Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.; Danish Diabetes Academy, Odense University Hospital, Odense, Denmark., Tencerova M; Molecular Endocrinology and Stem Cell Research Unit (KMEB), Department of Endocrinology and Metabolism, Odense University Hospital and Department of Clinical Research, University of Southern Denmark, Odense, Denmark., Nielsen R; Functional Genomics and Metabolism Research Unit, Department of Biochemistry and Molecular Biology, University of Southern Denmark, Odense, Denmark., Larsen BD; Functional Genomics and Metabolism Research Unit, Department of Biochemistry and Molecular Biology, University of Southern Denmark, Odense, Denmark., Röttger R; Department of Mathematics and Computer Science, University of Southern Denmark, Odense, Denmark., Baumbach J; Department of Mathematics and Computer Science, University of Southern Denmark, Odense, Denmark.; Experimental Bioinformatics, TUM School of Life Sciences, Technical University of Munich, Freising-Weihenstephan, Germany., Scheele C; Centre of Inflammation and Metabolism and Centre for Physical Activity Research, Rigshospitalet, University Hospital of Copenhagen, Copenhagen, Denmark.; Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark., Kassem M; Molecular Endocrinology and Stem Cell Research Unit (KMEB), Department of Endocrinology and Metabolism, Odense University Hospital and Department of Clinical Research, University of Southern Denmark, Odense, Denmark., Mandrup S; Functional Genomics and Metabolism Research Unit, Department of Biochemistry and Molecular Biology, University of Southern Denmark, Odense, Denmark. s.mandrup@bmb.sdu.dk.
Jazyk: angličtina
Zdroj: Nature genetics [Nat Genet] 2019 Apr; Vol. 51 (4), pp. 716-727. Date of Electronic Publication: 2019 Mar 04.
DOI: 10.1038/s41588-019-0359-1
Abstrakt: 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.
Databáze: MEDLINE
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