The Regulatory Landscape of Osteogenic Differentiation

Håkelien, Anne Mari; Bryne, Jan Christian; Harstad, Kristine G.; Lorenz, Susanne; Paulsen, Jonas; Sun, Jinchang; Mikkelsen, Tarjei S.; Myklebost, Ola; Meza‐Zepeda, Leonardo A.

doi:10.1002/stem.1759

Cited by 89 publications

(98 citation statements)

References 72 publications

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“…5B, we found that these histone marks followed the expected genomic distribution profiles when all gene bodies throughout the genome are averaged together to display the ChIP-seq tag densities as reported previously (54). During differentiation, peaks shifted in amplitude (greater or lesser peak reads) but not necessarily in location, similar to recent observations (55). This was demonstrated in Fig.…”

Section: Msc Differentiation Is Driven By Specific and Unique Transcrsupporting

confidence: 87%

Epigenetic Plasticity Drives Adipogenic and Osteogenic Differentiation of Marrow-derived Mesenchymal Stem Cells

Meyer

Benkusky

Sen

et al. 2016

Journal of Biological Chemistry

157

124

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Terminal differentiation of multipotent stem cells is achieved through a coordinated cascade of activated transcription factors and epigenetic modifications that drive gene transcription responsible for unique cell fate. Within the mesenchymal lineage, factors such as RUNX2 and PPAR␥ are indispensable for osteogenesis and adipogenesis, respectively. We therefore investigated genomic binding of transcription factors and accompanying epigenetic modifications that occur during osteogenic and adipogenic differentiation of mouse bone marrow-derived mesenchymal stem cells (MSCs). As assessed by ChIP-sequencing and RNA-sequencing analyses, we found that genes vital for osteogenic identity were linked to RUNX2, C/EBP␤, retinoid X receptor, and vitamin D receptor binding sites, whereas adipocyte differentiation favored PPAR␥, retinoid X receptor, C/EBP␣, and C/EBP␤ binding sites. Epigenetic marks were clear predictors of active differentiation loci as well as enhancer activities and selective gene expression. These marrow-derived MSCs displayed an epigenetic pattern that suggested a default preference for the osteogenic pathway; however, these patterns were rapidly altered near the Adipoq, Cidec, Fabp4, Lipe, Plin1, Pparg, and Cebpa genes during adipogenic differentiation. Surprisingly, we found that these cells also exhibited an epigenetic plasticity that enabled them to transdifferentiate from adipocytes to osteoblasts (and vice versa) after commitment, as assessed by staining, gene expression, and ChIP-quantitative PCR analysis. The osteogenic default pathway may be subverted during pathological conditions, leading to skeletal fragility and increased marrow adiposity during aging, estrogen deficiency, and skeletal unloading. Taken together, our data provide an increased mechanistic understanding of the epigenetic programs necessary for multipotent differentiation of MSCs that may prove beneficial in the development of therapeutic strategies.

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Section: Msc Differentiation Is Driven By Specific and Unique Transcrsupporting

confidence: 87%

Epigenetic Plasticity Drives Adipogenic and Osteogenic Differentiation of Marrow-derived Mesenchymal Stem Cells

Meyer

Benkusky

Sen

et al. 2016

Journal of Biological Chemistry

157

124

View full text Add to dashboard Cite

show abstract

“…We used ChIP-seq experiments generated in Gm12878, HelaS3, H1hesc, K562, and MCF7 cell lines. ChIP-seq data for Runx1 and Runx2 were retrieved from the NCBI Gene Expression Omnibus database (Edgar et al, 2002), with accession number GSE45144 for Runx1 in human hematopoietic stem and progenitor cells (HSPCs) (Beck et al, 2013), and GSE49585 for Runx2 in cultured human osteoblasts (Hakelien et al, 2014). …”

Section: Methodsmentioning

confidence: 99%

Divergence in DNA Specificity among Paralogous Transcription Factors Contributes to Their Differential In Vivo Binding

et al. 2018

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SUMMARY Paralogous transcription factors (TFs) are oftentimes reported to have identical DNA-binding motifs, despite the fact that they perform distinct regulatory functions. Differential genomic targeting by paralogous TFs is generally assumed to be due to interactions with protein co-factors or the chromatin environment. Using a computational-experimental framework called iMADS (integrative modeling and analysis of differential specificity), we show that, contrary to previous assumptions, paralogous TFs bind differently to genomic target sites even in vitro. We used iMADS to quantify, model, and analyze specificity differences between 11 TFs from 4 protein families. We found that paralogous TFs have diverged mainly at mediumand low-affinity sites, which are poorly captured by current motif models. We identify sequence and shape features differentially preferred by paralogous TFs, and we show that the intrinsic differences in specificity among paralogous TFs contribute to their differential in vivo binding. Thus, our study represents a step forward in deciphering the molecular mechanisms of differential specificity in TF families.

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“…The iMSC#3 GM group consisted of the experiment accession ERX302478 (run accession ERR329500) and ERX302479 (run accession ERR329502) while the iMSC#3 DM group contained theexperiment accession ERX302480 (run accession ERR329501) and ERX302481 (run accession ERR329499). RNA libraries were sequenced with the Illumina Genome Analyzer II system according to the manufacturer protocols (FC-104-5001; Illumina, San Diego, CA, USA), by performing a paired-end run with 75 bp read length for all samples (Hakelien et al, 2014) .…”

Section: Datasetsmentioning

confidence: 99%

Identification of long non-coding RNA involved in osteogenic differentiation from mesenchymal stem cells using RNA-Seq data

Song¹,

Gu²,

Qian³

et al. 2015

Genet. Mol. Res.

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ABSTRACT. The aim of this study was to identify long non-coding RNA (lncRNA) associated with osteogenic differentiation from mesenchymal stem cells (MSCs) using high-throughput RNA sequencing (RNA-Seq) data. RNA-Seq dataset was obtained from the European Bioinformatics Institute (accession No. PRJEB4496), including two replicates each for immortalized mesenchymal stem cells iMSC#3 cultured in growth medium (GM) and differentiation medium (DM) for 28 days. The clean reads were aligned to a hg19 reference genome by Tophat and assembled by Cufflinks to identify the known and novel transcripts. RPKM values were calculated to screen for differentially expressed RNA. Novel lncRNA were screened based on various filter criteria. Subsequently, the underlying function of novel lncRNAs were predicted by functional annotation by ERPIN, a coexpression network was constructed by WGCNA and the KEGG pathway enriched by KOBAS. A total of 3171 RNA differentially expressed between the DM and GM groups (2597 mRNA and 574 lncRNA) were identified. Among the 574 differentially expressed lncRNA, 357 were known and 217 were novel lncRNA. Furthermore, 32 novel lncRNA were found to be miRNA precursors (including miR-689, miR-640, miR-601, and miR-544). A total of 18269 ©FUNPEC-RP www.funpecrp.com.br Genetics and Molecular Research 14 (4): 18268-18279 (2015) Identifying lncRNA affecting osteogenic differentiation 14,275 co-expression relationships and 217 co-expression networks were obtained between novel lncRNA and mRNA. The differentially expressed lncRNA and mRNA were enriched into 6 significant pathways, including those for cancer, ECM-receptor interaction, and focal adhesion. Therefore, novel lncRNAwere identified and their underlying function predicted, which may provide the basis for future analyses of the role of lncRNA in osteoblastic differentiation.

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The Regulatory Landscape of Osteogenic Differentiation

Cited by 89 publications

References 72 publications

Epigenetic Plasticity Drives Adipogenic and Osteogenic Differentiation of Marrow-derived Mesenchymal Stem Cells

Epigenetic Plasticity Drives Adipogenic and Osteogenic Differentiation of Marrow-derived Mesenchymal Stem Cells

Divergence in DNA Specificity among Paralogous Transcription Factors Contributes to Their Differential In Vivo Binding

Identification of long non-coding RNA involved in osteogenic differentiation from mesenchymal stem cells using RNA-Seq data

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