title: Chromatin dynamics regulate mesenchymal stem cell lineage specification and differentiation to osteogenesis.
abstract: Multipotent mesenchymal stromal cells (MSCs) are critical for regeneration of multiple tissues. Epigenetic mechanisms are fundamental regulators of lineage specification and cell fate, and as such, we addressed the question of which epigenetic modifications characterize the transition of nascent MSCs to a tissue specific MSC-derived phenotype. By profiling the temporal changes of seven histone marks correlated to gene expression during proliferation, early commitment, matrix deposition, and mineralization stages, we identified distinct epigenetic mechanisms that regulate transcriptional programs necessary for tissue-specific phenotype development. Patterns of stage-specific enrichment of histone modifications revealed distinct modes of repression and activation of gene expression that would not be detected using single endpoint analysis. We discovered that at commitment, H3K27me3 is removed from genes that are upregulated and is not acquired on downregulated genes. Additionally, we found that the absence of H3K4me3 modification at promoters defined a subset of osteoblast-specific upregulated genes, indicating that acquisition of acetyl modifications drive activation of these genes. Significantly, loss or gain of H3K36me3 was the primary predictor of dynamic changes in temporal gene expression. Using unsupervised pattern discovery analysis the signature of osteogenic-related histone modifications identified novel functional cis regulatory modules associated with enhancer regions that control tissue-specific genes. Our work provides a cornerstone to understand the epigenetic regulation of transcriptional programs that are important for MSC lineage commitment and lineage, as well as insights to facilitate MSC-based therapeutic interventions.
authors.affiliation: Department of Biochemistry and Vermont Cancer Center, University of Vermont, Burlington, VT, United States. Electronic address: Hai.wu@uvm.edu.
authors.forename: Hai
authors.initials: H
authors.lastname: Wu
authors.affiliation: Department of Biochemistry and Vermont Cancer Center, University of Vermont, Burlington, VT, United States. Electronic address: Jonathan.A.Gordon@uvm.edu.
authors.forename: Jonathan A R
authors.initials: JA
authors.lastname: Gordon
authors.affiliation: Department of Cell and Developmental Biology, University of Massachusetts Medical School, Worcester, MA, United States. Electronic address: Troy.Whitfield@umassmed.edu.
authors.forename: Troy W
authors.initials: TW
authors.lastname: Whitfield
authors.affiliation: Department of Biochemistry and Vermont Cancer Center, University of Vermont, Burlington, VT, United States. Electronic address: Phillip.Tai@umassmed.edu.
authors.forename: Phillip W L
authors.initials: PW
authors.lastname: Tai
authors.affiliation: Department of Orthopedic Surgery, Mayo Clinic, Rochester, MN, United States. Electronic address: vanwijnen.andre@mayo.edu.
authors.forename: Andre J
authors.initials: AJ
authors.lastname: van Wijnen
authors.affiliation: Department of Biochemistry and Vermont Cancer Center, University of Vermont, Burlington, VT, United States. Electronic address: Janet.Stein@uvm.edu.
authors.forename: Janet L
authors.initials: JL
authors.lastname: Stein
authors.affiliation: Department of Biochemistry and Vermont Cancer Center, University of Vermont, Burlington, VT, United States. Electronic address: Gary.Stein@uvm.edu.
authors.forename: Gary S
authors.initials: GS
authors.lastname: Stein
authors.affiliation: Department of Biochemistry and Vermont Cancer Center, University of Vermont, Burlington, VT, United States. Electronic address: Jane.Lian@uvm.edu.
authors.forename: Jane B
authors.initials: JB
authors.lastname: Lian
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000235:genetics*; D019070:Cell Lineage / Q000235:genetics*; D042002:Chromatin Assembly and Disassembly / Q000235:genetics*; D044127:Epigenesis, Genetic; D020869:Gene Expression Profiling; D006657:Histones / Q000378:metabolism; D059630:Mesenchymal Stem Cells / Q000166:cytology* / Q000378:metabolism*; D051379:Mice; D010006:Osteoblasts / Q000166:cytology / Q000378:metabolism; D010012:Osteogenesis / Q000235:genetics*; D011499:Protein Processing, Post-Translational / Q000235:genetics; D014158:Transcription, Genetic
chemical_list: D006657:Histones
keywords: ChIP-Seq; Chromatin; Epigenetics; Epigenomics; Gene expression; Mesenchymal stromal cells; Osteoblast