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Genome-wide strategies identify molecular niches regulated by connective tissue-associated transcription factors

Mickael Orgeur, Marvin Martens, Georgeta Leonte, Sonya Nassari, Marie-Ange Bonnin, Stefan T. Börno, Bernd Timmermann, Jochen Hecht, Delphine Duprez, Sigmar Stricker
doi: https://doi.org/10.1101/165837
Mickael Orgeur
1Institute of Chemistry and Biochemistry, Freie Universität Berlin, Berlin, Germany
2Max Planck Institute for Molecular Genetics, Berlin, Germany
3Sorbonne Universités, UPMC Univ. Paris 06, CNRS UMR 7622, Inserm U1156, IBPS-Developmental Biology Laboratory, 75005 Paris, France
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Marvin Martens
3Sorbonne Universités, UPMC Univ. Paris 06, CNRS UMR 7622, Inserm U1156, IBPS-Developmental Biology Laboratory, 75005 Paris, France
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Georgeta Leonte
2Max Planck Institute for Molecular Genetics, Berlin, Germany
4Institute of Biology, Freie Universität Berlin, Berlin, Germany
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Sonya Nassari
3Sorbonne Universités, UPMC Univ. Paris 06, CNRS UMR 7622, Inserm U1156, IBPS-Developmental Biology Laboratory, 75005 Paris, France
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Marie-Ange Bonnin
3Sorbonne Universités, UPMC Univ. Paris 06, CNRS UMR 7622, Inserm U1156, IBPS-Developmental Biology Laboratory, 75005 Paris, France
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Stefan T. Börno
2Max Planck Institute for Molecular Genetics, Berlin, Germany
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Bernd Timmermann
2Max Planck Institute for Molecular Genetics, Berlin, Germany
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Jochen Hecht
2Max Planck Institute for Molecular Genetics, Berlin, Germany
5Berlin-Brandenburg Center for Regenerative Therapies (BCRT), Charité Universitatsmedizin, Berlin, Germany
6Centre for Genomic Regulation (CRG), The Barcelona Institute for Science and Technology, Dr. Aiguader 88, 08003 Barcelona, Spain
7Universitat Pompeu Fabra (UPF), Barcelona, Spain
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Delphine Duprez
3Sorbonne Universités, UPMC Univ. Paris 06, CNRS UMR 7622, Inserm U1156, IBPS-Developmental Biology Laboratory, 75005 Paris, France
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  • For correspondence: sigmar.stricker@fu-berlin.de duprez@upmc.fr
Sigmar Stricker
1Institute of Chemistry and Biochemistry, Freie Universität Berlin, Berlin, Germany
2Max Planck Institute for Molecular Genetics, Berlin, Germany
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  • For correspondence: sigmar.stricker@fu-berlin.de duprez@upmc.fr
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Abstract

Background Connective tissues support, connect and separate tissues and organs, playing crucial roles in development, homeostasis and fibrosis. Cell specification and differentiation is triggered by the activity of specific transcription factors. While key transcription factors have been identified for differentiation processes of most tissues, connective tissue differentiation remains largely unstudied.

Results To gain insight into the regulatory cascades involved in connective tissue differentiation, we selected five zinc finger transcription factors - OSR1, OSR2, EGR1, KLF2 and KLF4 - based on their expression patterns and/or known involvement in the differentiation of mesenchymal cells into connective tissue subtypes. We combined RNA-seq with ChIP-seq profiling in chick limb cells following overexpression of individual transcription factors. We identified a set of common genes regulated by all five transcription factors, which constitutes a connective tissue core expression set. This common core was enriched in genes associated with axon guidance and myofibroblast signature. In addition, each of the transcription factors regulated a different set of extracellular matrix components and signalling molecules, which define local molecular niches important for connective tissue development and function.

Conclusions The established regulatory network identifies common and distinct molecular signatures downstream of five connective tissue-associated transcription factors and provides insight into the signalling pathways governing limb connective tissue differentiation. It also suggests a concept whereby local molecular niches can be created via the expression of specific transcription factors impinging on the specification of microenvironments.

Footnotes

  • List of abbreviations 3F, triple-FLAG; chMM, chick micromass; CDS, coding sequence; ChIP-seq, chromatin immunoprecipitation followed by massively parallel DNA sequencing; CT, connective tissue; DE, differentially expressed; ECM, extracellular matrix; FDR, false-discovery rate; GO, gene ontology; IDR, irreproducibility discovery rate; padj, Benjamini-Hochberg adjusted p-value; PCA, principal components analysis; rlog; regularized logarithm; RNA-seq, whole-transcriptome sequencing; TF, transcription factor; TFBS, transcription factor binding sites; TPM, transcripts per million; TSS, transcriptional start site.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC 4.0 International license.
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Posted July 20, 2017.
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Genome-wide strategies identify molecular niches regulated by connective tissue-associated transcription factors
Mickael Orgeur, Marvin Martens, Georgeta Leonte, Sonya Nassari, Marie-Ange Bonnin, Stefan T. Börno, Bernd Timmermann, Jochen Hecht, Delphine Duprez, Sigmar Stricker
bioRxiv 165837; doi: https://doi.org/10.1101/165837
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Genome-wide strategies identify molecular niches regulated by connective tissue-associated transcription factors
Mickael Orgeur, Marvin Martens, Georgeta Leonte, Sonya Nassari, Marie-Ange Bonnin, Stefan T. Börno, Bernd Timmermann, Jochen Hecht, Delphine Duprez, Sigmar Stricker
bioRxiv 165837; doi: https://doi.org/10.1101/165837

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