PT  - JOURNAL ARTICLE
AU  - Mickael Orgeur
AU  - Marvin Martens
AU  - Georgeta Leonte
AU  - Sonya Nassari
AU  - Marie-Ange Bonnin
AU  - Stefan T. Börno
AU  - Bernd Timmermann
AU  - Jochen Hecht
AU  - Delphine Duprez
AU  - Sigmar Stricker
TI  - Genome-wide strategies identify molecular niches regulated by connective tissue-associated transcription factors
AID  - 10.1101/165837
DP  - 2017 Jan 01
TA  - bioRxiv
PG  - 165837
4099  - http://biorxiv.org/content/early/2017/07/20/165837.short
4100  - http://biorxiv.org/content/early/2017/07/20/165837.full
AB  - 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.