Back to Search
Start Over
Synergistic co-regulation and competition by a SOX9-GLI-FOXA phasic transcriptional network coordinate chondrocyte differentiation transitions
- Source :
- PLoS Genetics, PLoS Genetics, Vol 14, Iss 4, p e1007346 (2018)
- Publication Year :
- 2018
- Publisher :
- Public Library of Science, 2018.
-
Abstract
- The growth plate mediates bone growth where SOX9 and GLI factors control chondrocyte proliferation, differentiation and entry into hypertrophy. FOXA factors regulate hypertrophic chondrocyte maturation. How these factors integrate into a Gene Regulatory Network (GRN) controlling these differentiation transitions is incompletely understood. We adopted a genome-wide whole tissue approach to establish a Growth Plate Differential Gene Expression Library (GP-DGEL) for fractionated proliferating, pre-hypertrophic, early and late hypertrophic chondrocytes, as an overarching resource for discovery of pathways and disease candidates. De novo motif discovery revealed the enrichment of SOX9 and GLI binding sites in the genes preferentially expressed in proliferating and prehypertrophic chondrocytes, suggesting the potential cooperation between SOX9 and GLI proteins. We integrated the analyses of the transcriptome, SOX9, GLI1 and GLI3 ChIP-seq datasets, with functional validation by transactivation assays and mouse mutants. We identified new SOX9 targets and showed SOX9-GLI directly and cooperatively regulate many genes such as Trps1, Sox9, Sox5, Sox6, Col2a1, Ptch1, Gli1 and Gli2. Further, FOXA2 competes with SOX9 for the transactivation of target genes. The data support a model of SOX9-GLI-FOXA phasic GRN in chondrocyte development. Together, SOX9-GLI auto-regulate and cooperate to activate and repress genes in proliferating chondrocytes. Upon hypertrophy, FOXA competes with SOX9, and control toward terminal differentiation passes to FOXA, RUNX, AP1 and MEF2 factors.<br />Author summary In the development of the mammalian growth plate, while several transcription factors are individually well known for their key roles in regulating phases of chondrocyte differentiation, there is little information on how they interact and cooperate with each other. We took an unbiased genome wide approach to identify the transcription factors and signaling pathways that play dominant roles in the chondrocyte differentiation cascade. We developed a searchable library of differentially expressed genes, GP-DGEL, which has fine spatial resolution and global transcriptomic coverage for discovery of processes, pathways and disease candidates. Our work identifies a novel regulatory mechanism that integrates the action of three transcription factors, SOX9, GLI and FOXA. SOX9-GLI auto-regulate and cooperate to activate and repress genes in proliferating chondrocytes. Upon entry into prehypertrophy, FOXA competes with SOX9, and control of hypertrophy passes to FOXA, RUNX, AP1 and MEF2 factors.
- Subjects :
- 0301 basic medicine
Cancer Research
Cellular differentiation
Gene Expression
Transactivation
Database and Informatics Methods
Mice
0302 clinical medicine
Cell Signaling
Animal Cells
Transcriptional regulation
Medicine and Health Sciences
Gene Regulatory Networks
Growth Plate
Genetics (clinical)
Connective Tissue Cells
Regulation of gene expression
Bone growth
integumentary system
MEF2 Transcription Factors
Physics
Transcriptional Control
Cell Differentiation
SOX9 Transcription Factor
musculoskeletal system
Cell biology
Physical sciences
AP-1 transcription factor
Chemistry
medicine.anatomical_structure
Connective Tissue
embryonic structures
Hepatocyte Nuclear Factor 3-beta
Female
Anatomy
Cellular Types
Sequence Analysis
Chondrogenesis
Research Article
Signal Transduction
Mef2
Transcriptional Activation
endocrine system
animal structures
lcsh:QH426-470
Bioinformatics
Chemical physics
Biology
Research and Analysis Methods
Models, Biological
Zinc Finger Protein GLI1
Chondrocyte
03 medical and health sciences
Chondrocytes
Sequence Motif Analysis
medicine
Genetics
Animals
Gene Regulation
Bone
Molecular Biology
Ecology, Evolution, Behavior and Systematics
Bone Development
SOX9-GLI-FOXA phasic transcriptional network
Biology and Life Sciences
Core Binding Factor alpha Subunits
Dimers (Chemical physics)
Cell Biology
Mice, Inbred C57BL
lcsh:Genetics
030104 developmental biology
Biological Tissue
Cartilage
Hedgehog Signaling
Mice, Inbred CBA
030217 neurology & neurosurgery
Subjects
Details
- Language :
- English
- ISSN :
- 15537404 and 15537390
- Volume :
- 14
- Issue :
- 4
- Database :
- OpenAIRE
- Journal :
- PLoS Genetics
- Accession number :
- edsair.doi.dedup.....5af65c69e44daadf3530596849a8204a