Functional Genomics and Metabolism Research Unit, Department of Biochemistry and Molecular Biology, University of Southern Denmark, Odense, Denmark.
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.
Nat Genet. 2019 Apr;51(4):716-727. doi: 10.1038/s41588-019-0359-1. Epub 2019 Mar 4.
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.
间充质（基质）干细胞（MSCs）构成中胚层多能细胞群体，参与许多不同器官的组织再生和稳态维持。在这里，我们对与人类 MSC 的成骨细胞和脂肪细胞分化相关的转录组和表观基因组变化进行了全面表征。我们证明脂肪生成是由染色质景观的大量重塑和增强子的从头激活驱动的，而成骨生成涉及预先建立的增强子的激活。使用用于转录调控的计算机模拟的机器学习算法，我们确定了一个大而多样化的促成骨和成脂转录因子的转录网络。有趣的是，这些因子的结合基序与与人类骨和脂肪形成相关的 SNP 重叠，并且该网络的单个成员的敲低足以在两个方向上调节分化，这表明谱系决定是许多不同转录因子的活性之间的微妙平衡。
