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Nat Genet. 2019 Apr;51(4):716-727. doi: 10.1038/s41588-019-0359-1. Epub 2019 Mar 4.

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

Author information

1
Functional Genomics and Metabolism Research Unit, Department of Biochemistry and Molecular Biology, University of Southern Denmark, Odense, Denmark.
2
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.
3
Department of Mathematics and Computer Science, University of Southern Denmark, Odense, Denmark.
4
Centre of Inflammation and Metabolism and Centre for Physical Activity Research, Rigshospitalet, University Hospital of Copenhagen, Copenhagen, Denmark.
5
Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
6
Danish Diabetes Academy, Odense University Hospital, Odense, Denmark.
7
Experimental Bioinformatics, TUM School of Life Sciences, Technical University of Munich, Freising-Weihenstephan, Germany.
8
Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark.
9
Functional Genomics and Metabolism Research Unit, Department of Biochemistry and Molecular Biology, University of Southern Denmark, Odense, Denmark. s.mandrup@bmb.sdu.dk.

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.

PMID:
30833796
DOI:
10.1038/s41588-019-0359-1
[Indexed for MEDLINE]

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