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Temporal enhancer profiling of parallel lineages identifies AHR and GLIS1 as regulators of mesenchymal multipotency.

ABSTRACT: Temporal data on gene expression and context-specific open chromatin states can improve identification of key transcription factors (TFs) and the gene regulatory networks (GRNs) controlling cellular differentiation. However, their integration remains challenging. Here, we delineate a general approach for data-driven and unbiased identification of key TFs and dynamic GRNs, called EPIC-DREM. We generated time-series transcriptomic and epigenomic profiles during differentiation of mouse multipotent bone marrow stromal cell line (ST2) toward adipocytes and osteoblasts. Using our novel approach we constructed time-resolved GRNs for both lineages and identifed the shared TFs involved in both differentiation processes. To take an alternative approach to prioritize the identified shared regulators, we mapped dynamic super-enhancers in both lineages and associated them to target genes with correlated expression profiles. The combination of the two approaches identified aryl hydrocarbon receptor (AHR) and Glis family zinc finger 1 (GLIS1) as mesenchymal key TFs controlled by dynamic cell type-specific super-enhancers that become repressed in both lineages. AHR and GLIS1 control differentiation-induced genes and their overexpression can inhibit the lineage commitment of the multipotent bone marrow-derived ST2 cells.

SUBMITTER: Gerard D

PROVIDER: S-EPMC6380961 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature

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Temporal enhancer profiling of parallel lineages identifies AHR and GLIS1 as regulators of mesenchymal multipotency.

Gérard Deborah D Schmidt Florian F Ginolhac Aurélien A Schmitz Martine M Halder Rashi R Ebert Peter P Schulz Marcel H MH Sauter Thomas T Sinkkonen Lasse L

Nucleic acids research 20190201 3

Temporal data on gene expression and context-specific open chromatin states can improve identification of key transcription factors (TFs) and the gene regulatory networks (GRNs) controlling cellular differentiation. However, their integration remains challenging. Here, we delineate a general approach for data-driven and unbiased identification of key TFs and dynamic GRNs, called EPIC-DREM. We generated time-series transcriptomic and epigenomic profiles during differentiation of mouse multipotent ...[more]

PMID: 30544251

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Project description:Differentiation of multipotent mesenchymal stem cells into bone-forming osteoblasts requires strict coordination of transcriptional pathways. Aryl hydrocarbon receptor (AhR) ligands, such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), have been shown to alter osteoblast differentiation in vitro and bone formation in multiple developmental in vivo models. The goal of the present study was to establish a global transcriptomic landscape during early, intermediate, and apical stages of osteogenic differentiation in vitro in response to TCDD exposure. Human bone-derived mesenchymal stem cells (hBMSC) were cultured in growth media (GM), osteogenic differentiation media (ODM), or osteogenic differentiation media containing 10 nM TCDD (ODM+TCDD), thus enabling a comparison of the transcriptomic profiles of undifferentiated, differentiated, and differentiated -TCDD-exposed hBMSCs, respectively. In this test system, exposure to TCDD attenuated differentiation of hBMSCs into osteoblasts as evidenced by reduced alkaline phosphatase activity and mineralization. At various timepoints, we observed altered expression of genes that play a role in the Wnt, FGF, BMP/TGF-β developmental pathways, as well as pathways related to extracellular matrix organization and deposition. Reconstruction of gene regulatory networks with the iDREM analysis revealed modulation of transcription factors (TF) including POLR3G, NR4A1, RDBP, GTF2B, POU2F2 and ZEB1, which may putatively influence osteoblast differentiation and the requisite deposition and mineralization of bone extracellular matrix. We demonstrate that the combination of RNA-Seq data in conjunction with the iDREM regulatory model, captures the transcriptional dynamics underlying mesenchymal stem cell differentiation under different conditions in vitro. Model predictions are consistent with existing knowledge and provides a new tool to identify novel pathways and transcription factors that may facilitate a better understanding of the osteoblast differentiation process, perturbation by exogenous agents, and potential intervention strategies targeting those specific pathways.

Dataset Information

Temporal enhancer profiling of parallel lineages identifies AHR and GLIS1 as regulators of mesenchymal multipotency.

Publications

Temporal enhancer profiling of parallel lineages identifies AHR and GLIS1 as regulators of mesenchymal multipotency.

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