The transcription factors SOX9 and SOX5/SOX6 cooperate genome-wide through super-enhancers to drive chondrogenesis

SOX9 is a transcriptional activator required for chondrogenesis, and SOX5 and SOX6 are closely related DNA-binding proteins that critically enhance its function. We use here genome-wide approaches to gain novel insights into the full spectrum of the target genes and modes of action of this chondroge...

Full description

Saved in:
Bibliographic Details
Published inNucleic acids research Vol. 43; no. 17; pp. 8183 - 8203
Main Authors Liu, Chia-Feng, Lefebvre, Véronique
Format Journal Article
LanguageEnglish
Published England Oxford University Press 30.09.2015
Subjects
Animals
Cell Line, Tumor
Cell Proliferation
Cercopithecus aethiops
Chondrocytes - metabolism
Chondrogenesis - genetics
COS Cells
Enhancer Elements, Genetic
Female
Gene Expression
Gene regulation, Chromatin and Epigenetics
Genome
Growth Plate - cytology
HEK293 Cells
Humans
Mice
Rats
SOX9 Transcription Factor - metabolism
SOXD Transcription Factors - metabolism
Online AccessGet full text

Cover

More Information
Summary:SOX9 is a transcriptional activator required for chondrogenesis, and SOX5 and SOX6 are closely related DNA-binding proteins that critically enhance its function. We use here genome-wide approaches to gain novel insights into the full spectrum of the target genes and modes of action of this chondrogenic trio. Using the RCS cell line as a faithful model for proliferating/early prehypertrophic growth plate chondrocytes, we uncover that SOX6 and SOX9 bind thousands of genomic sites, frequently and most efficiently near each other. SOX9 recognizes pairs of inverted SOX motifs, whereas SOX6 favors pairs of tandem SOX motifs. The SOX proteins primarily target enhancers. While binding to a small fraction of typical enhancers, they bind multiple sites on almost all super-enhancers (SEs) present in RCS cells. These SEs are predominantly linked to cartilage-specific genes. The SOX proteins effectively work together to activate these SEs and are required for in vivo expression of their associated genes. These genes encode key regulatory factors, including the SOX trio proteins, and all essential cartilage extracellular matrix components. Chst11, Fgfr3, Runx2 and Runx3 are among many other newly identified SOX trio targets. SOX9 and SOX5/SOX6 thus cooperate genome-wide, primarily through SEs, to implement the growth plate chondrocyte differentiation program.
Bibliography:ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
content type line 23
ISSN:0305-1048
1362-4962
DOI:10.1093/nar/gkv688