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

Research output: Contribution to journalJournal articleResearchpeer-review

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
JournalNature Genetics
Volume51
Issue number4
Pages (from-to)716-727
ISSN1061-4036
DOIs
Publication statusPublished - Apr 2019

Fingerprint

Adipogenesis
Stem Cell Factor
Mesenchymal Stromal Cells
Osteogenesis
Chromatin Assembly and Disassembly
Stromal Cells
Osteoblasts
Adipocytes
Epigenomics
Computer Simulation
Single Nucleotide Polymorphism
Homeostasis
Fats
Population
Direction compound

Cite this

@article{57415ee6ea3843049257906180b0381c,
title = "Osteogenesis depends on commissioning of a network of stem cell transcription factors that act as repressors of adipogenesis",
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.",
author = "Alexander Rauch and Haakonsson, {Anders K} and Madsen, {Jesper G S} and Mette Larsen and Isabel Forss and Madsen, {Martin R} and {Van Hauwaert}, {Elvira L} and Christian Wiwie and Jespersen, {Naja Z} and Michaela Tencerova and Ronni Nielsen and Larsen, {Bj{\o}rk D} and Richard R{\"o}ttger and Jan Baumbach and Camilla Scheele and Moustapha Kassem and Susanne Mandrup",
year = "2019",
month = "4",
doi = "10.1038/s41588-019-0359-1",
language = "English",
volume = "51",
pages = "716--727",
journal = "Nature Genetics",
issn = "1061-4036",
publisher = "Nature Publishing Group",
number = "4",

}

TY - JOUR

T1 - Osteogenesis depends on commissioning of a network of stem cell transcription factors that act as repressors of adipogenesis

AU - Rauch, Alexander

AU - Haakonsson, Anders K

AU - Madsen, Jesper G S

AU - Larsen, Mette

AU - Forss, Isabel

AU - Madsen, Martin R

AU - Van Hauwaert, Elvira L

AU - Wiwie, Christian

AU - Jespersen, Naja Z

AU - Tencerova, Michaela

AU - Nielsen, Ronni

AU - Larsen, Bjørk D

AU - Röttger, Richard

AU - Baumbach, Jan

AU - Scheele, Camilla

AU - Kassem, Moustapha

AU - Mandrup, Susanne

PY - 2019/4

Y1 - 2019/4

N2 - 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.

AB - 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.

UR - https://doi.org/10.1038/s41588-019-0359-1

U2 - 10.1038/s41588-019-0359-1

DO - 10.1038/s41588-019-0359-1

M3 - Journal article

VL - 51

SP - 716

EP - 727

JO - Nature Genetics

JF - Nature Genetics

SN - 1061-4036

IS - 4

ER -