title: The regulatory landscape of osteogenic differentiation.
abstract: 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.
authors.affiliation: Department of Tumor Biology, Institute for Cancer Research, The Norwegian Radium Hospital.
authors.forename: Anne-Mari
authors.initials: AM
authors.lastname: Håkelien
authors.forename: Jan Christian
authors.initials: JC
authors.lastname: Bryne
authors.forename: Kristine G
authors.initials: KG
authors.lastname: Harstad
authors.forename: Susanne
authors.initials: S
authors.lastname: Lorenz
authors.forename: Jonas
authors.initials: J
authors.lastname: Paulsen
authors.forename: Jinchang
authors.initials: J
authors.lastname: Sun
authors.forename: Tarjei S
authors.initials: TS
authors.lastname: Mikkelsen
authors.forename: Ola
authors.initials: O
authors.lastname: Myklebost
authors.forename: Leonardo A
authors.initials: LA
authors.lastname: Meza-Zepeda
mesh_terms: D017398:Alternative Splicing / Q000235:genetics; D001483:Base Sequence; D001665:Binding Sites; D002454:Cell Differentiation / Q000235:genetics*; D019070:Cell Lineage / Q000235:genetics; D002843:Chromatin / Q000378:metabolism; D050659:Core Binding Factor Alpha 1 Subunit / Q000235:genetics / Q000378:metabolism; D044127:Epigenesis, Genetic; D015894:Genome, Human / Q000235:genetics; D006801:Humans; D059630:Mesenchymal Stem Cells / Q000166:cytology; D008969:Molecular Sequence Data; D010012:Osteogenesis / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism
chemical_list: D002843:Chromatin; D050659:Core Binding Factor Alpha 1 Subunit; D012333:RNA, Messenger
keywords: Differentiation; Epigenomics; Mesenchymal stem cells; Osteogenesis; RUNX2; Transcription factors