Article

Sox9 and p300 cooperatively regulate chromatin-mediated transcription.

Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, California 92037, USA.
Journal of Biological Chemistry (impact factor: 4.77). 11/2005; 280(42):35203-8. DOI:10.1074/jbc.M502409200 pp.35203-8
Source: PubMed

ABSTRACT Chromatin structure is a fundamental component of gene regulation, expression, and cellular differentiation. We have previously reported that the multifunctional coactivator p300 is a member of the Sox9 (Sry-type high mobility group box 9)-related transcriptional apparatus and activates Sox9-dependent transcription during chondrogenesis. However, the mechanism of synergy between Sox9 and p300 in chromatin-mediated transcription has not been elucidated. In the present study we investigated the activity of Sox9 and p300 on chromatinized templates in vitro. Recombinant Sox9 was shown to be associated with several transcriptional cofactors including p300. In vitro transcription assays revealed that p300 potentiated Sox9-dependent transcription on chromatinized DNA and, importantly, was associated with hyperacetylated histones. Consistent with these results, the histone deacetylase inhibitor trichostatin A stimulated the expression of Sox9-regulated cartilage matrix genes and induced histone acetylation around the enhancer region of the collagen alpha1 (II) gene in chondrocytes. These findings suggest that Sox9 interacts with chromatin and activates transcription via regulation of chromatin modification.

0 0
 · 
0 Bookmarks
 · 
41 Views
  • Source
    Article: Transcriptional regulation of chondrogenesis by coactivator Tip60 via chromatin association with Sox9 and Sox5.
    Takako Hattori, Francoise Coustry, Shelley Stephens, Heidi Eberspaecher, Masaharu Takigawa, Hideyo Yasuda, Benoit de Crombrugghe
    [show abstract] [hide abstract]
    ABSTRACT: Sox9 is a transcription factor of the SRY family required for several steps of chondrogenesis. It activates the expression of various chondrocyte-specific genes, but the mechanisms and role of cofactors involved in Sox9-regulated gene transcription are not fully understood. Here, we report on the characterization of a Tat interactive protein-60 (Tip60) as Sox9-associated protein identified in a yeast two-hybrid screen. Both in vitro and in vivo assays confirmed the specificity of interactions between Sox9 and Tip60 including the existence of an endogenous complex containing both polypeptides in chondrocytes. Gel shift assays showed the presence of a complex containing Sox9, Tip60 and the DNA of an enhancer region of the Col2a1 promoter. Reporter assays using a Col2a1 promoter with multimerized Col2a1 Sox9-binding sites indicated that Tip60 enhanced the transcriptional activity of Sox9. A larger Col2a1 promoter showed that Tip60 increased the activity of this promoter in the presence of both Sox9 and Sox5. Ectopic expression of Sox9 and transient-cotransfection with Tip60 in COS7 cells showed a more diffuse subnuclear colocalization, suggesting changes in the chromatin structure. Chromatin immunoprecipitation assays showed that Tip60, Sox9 and Sox5 associated with the same Col2a1 enhancer region. Consistent with a role of Tip60 in chondrogenesis, addition of Tip60 siRNA to limb-bud micromass cultures delayed chondrocyte differention. Tip60 enhances acetylation of Sox9 mainly through K61, 253, 398 residues; however, the K61/253/398A mutant of Sox9 still exhibited enhanced transcriptional activity by Tip60. Our results support the hypothesis that Tip60 is a coactivator of Sox9 in chondrocytes.
    Nucleic Acids Research 06/2008; 36(9):3011-24. · 8.03 Impact Factor
  • Source
    Article: Targeting histone deacetylases for the treatment of immune, endocrine & metabolic disorders.
    M W Lawless, S Norris, K J O'Byrne, S G Gray
    [show abstract] [hide abstract]
    ABSTRACT: The 'histone code' is a well-established hypothesis describing the idea that specific patterns of post-translational modifications to histones act like a molecular "code" recognised and used by non-histone proteins to regulate specific chromatin functions. One modification which has received significant attention is that of histone acetylation. The enzymes which regulate this modification are described as histone acetyltransferases or HATs, and histone deacetylases or HDACs [1]. Due to their conserved catalytic domain HDACs have been actively targeted as a therapeutic target. The pro-inflammatory environment is increasingly being recognised as a critical element for both degenerative diseases and cancer. The present review will discuss the current knowledge surrounding the clinical potential & current development of histone deacetylases for the treatment of diseases for which a proinflammatory environment plays important roles, and the molecular mechanisms by which such inhibitors may play important functions in modulating the proinflammatory environment.
    Endocrine Metabolic & Immune Disorders - Drug Targets(Formerly Current Drug Targets - Immune Endocrine & Metabolic Disorders) 03/2009; 9(1):84-107.
  • Source
    Article: Integrative analysis of genomic, functional and protein interaction data predicts long-range enhancer-target gene interactions.
    Christian Rödelsperger, Gao Guo, Mateusz Kolanczyk, Angelika Pletschacher, Sebastian Köhler, Sebastian Bauer, Marcel H Schulz, Peter N Robinson
    [show abstract] [hide abstract]
    ABSTRACT: Multicellular organismal development is controlled by a complex network of transcription factors, promoters and enhancers. Although reliable computational and experimental methods exist for enhancer detection, prediction of their target genes remains a major challenge. On the basis of available literature and ChIP-seq and ChIP-chip data for enhanceosome factor p300 and the transcriptional regulator Gli3, we found that genomic proximity and conserved synteny predict target genes with a relatively low recall of 12-27% within 2 Mb intervals centered at the enhancers. Here, we show that functional similarities between enhancer binding proteins and their transcriptional targets and proximity in the protein-protein interactome improve prediction of target genes. We used all four features to train random forest classifiers that predict target genes with a recall of 58% in 2 Mb intervals that may contain dozens of genes, representing a better than two-fold improvement over the performance of prediction based on single features alone. Genome-wide ChIP data is still relatively poorly understood, and it remains difficult to assign biological significance to binding events. Our study represents a first step in integrating various genomic features in order to elucidate the genomic network of long-range regulatory interactions.
    Nucleic Acids Research 11/2010; 39(7):2492-502. · 8.03 Impact Factor

Show more

Data provided are for informational purposes only. Although carefully collected, accuracy cannot be guaranteed. The impact factor represents a rough estimation of the journal's impact factor and does not reflect the actual current impact factor. Publisher conditions are provided by RoMEO. Differing provisions from the publisher's actual policy or licence agreement may be applicable.

Keywords

activates Sox9-dependent transcription
 
cellular differentiation
 
chromatin modification
 
collagen alpha1
 
enhancer region
 
fundamental component
 
histone deacetylase inhibitor trichostatin
 
hyperacetylated histones
 
induced histone acetylation
 
multifunctional coactivator p300
 
p300 potentiated Sox9-dependent transcription
 
Recombinant Sox9
 
Sox9
 
Sox9 interacts
 
Sox9-regulated cartilage matrix genes
 
transcriptional cofactors
 
vitro transcription assays
 

Takayuki Furumatsu