Open AccessThe Regulatory Landscape of Osteogenic Differentiation
Author(s) -
Håkelien AnneMari,
Bryne Jan Christian,
Harstad Kristine G.,
Lorenz Susanne,
Paulsen Jonas,
Sun Jinchang,
Mikkelsen Tarjei S.,
Myklebost Ola,
MezaZepeda Leonardo A.
Publication year - 2014
Publication title -
stem cells
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.159
H-Index - 229
eISSN - 1549-4918
pISSN - 1066-5099
DOI - 10.1002/stem.1759
Subject(s) - runx2 , biology , transcription factor , promoter , dna methylation , epigenetics , regulation of gene expression , cellular differentiation , histone , gene , mesenchymal stem cell , gene regulatory network , microbiology and biotechnology , genetics , cancer research , gene expression
Differentiation of osteoblasts from mesenchymal stem cells (MSCs) is an integral part of bone development and homeostasis, and may when improperly regulated cause disease such as bone cancer or osteoporosis. Using unbiased high‐throughput methods we here characterize the landscape of global changes in gene expression, histone modifications, and DNA methylation upon differentiation of human MSCs to the osteogenic lineage. Furthermore, we provide a first genome‐wide characterization of DNA binding sites of the bone master regulatory transcription factor Runt‐related transcription factor 2 (RUNX2) in human osteoblasts, revealing target genes associated with regulation of proliferation, migration, apoptosis, and with a significant overlap with p53 regulated genes. These findings expand on emerging evidence of a role for RUNX2 in cancer, including bone metastases, and the p53 regulatory network. We further demonstrate that RUNX2 binds to distant regulatory elements, promoters, and with high frequency to gene 3′ ends. Finally, we identify TEAD2 and GTF2I as novel regulators of osteogenesis. S tem C ells 2014;32:2780–2793