Freie Universität Berlin, Institute of Chemistry and Biochemistry, Thielallee 63, 14195 Berlin, Germany.
Max Planck Institute for Molecular Genetics, Ihnestr. 63-73, 14195 Berlin, Germany.
Development. 2018 Mar 29;145(7):dev161208. doi: 10.1242/dev.161208.
Connective tissues support organs and play crucial roles in development, homeostasis and fibrosis, yet our understanding of their formation is still limited. To gain insight into the molecular mechanisms of connective tissue specification, we selected five zinc-finger transcription factors - OSR1, OSR2, EGR1, KLF2 and KLF4 - based on their expression patterns and/or known involvement in connective tissue subtype differentiation. RNA-seq and ChIP-seq profiling of chick limb micromass cultures revealed a set of common genes regulated by all five transcription factors, which we describe as a connective tissue core expression set. This common core was enriched with genes associated with axon guidance and myofibroblast signature, including fibrosis-related genes. In addition, each transcription factor regulated a specific set of signalling molecules and extracellular matrix components. This suggests a concept whereby local molecular niches can be created by the expression of specific transcription factors impinging on the specification of local microenvironments. The regulatory network established here identifies common and distinct molecular signatures of limb connective tissue subtypes, provides novel insight into the signalling pathways governing connective tissue specification, and serves as a resource for connective tissue development.
结缔组织支持器官，并在发育、内稳态和纤维化中发挥关键作用，但我们对其形成的理解仍然有限。为了深入了解结缔组织特化的分子机制，我们根据表达模式和/或已知参与结缔组织亚型分化，选择了五个锌指转录因子——OSR1、OSR2、EGR1、KLF2 和 KLF4。对鸡肢芽微团培养物的 RNA-seq 和 ChIP-seq 分析揭示了一组由这五个转录因子共同调控的常见基因，我们将其描述为结缔组织核心表达组。这个共同的核心富含与轴突导向和肌成纤维细胞特征相关的基因，包括与纤维化相关的基因。此外，每个转录因子还调控了一组特定的信号分子和细胞外基质成分。这表明，特定转录因子的表达可以通过影响局部微环境的特化来创建局部分子生态位的概念。这里建立的调控网络确定了肢体结缔组织亚型的共同和独特的分子特征，为调控结缔组织特化的信号通路提供了新的见解，并为结缔组织发育提供了资源。
