Unknown,Transcriptomics,Genomics,Proteomics

Dataset Information

Transcription profiling of human colonic cells before and after induction of the transcription factor SOX9 by doxycycline

ABSTRACT: Transcriptome of modified HT29Cl.16E colonic cells before and after induction of the transcription factor SOX9 by doxycycline.

ORGANISM(S): Homo sapiens

SUBMITTER: Philippe Blache

PROVIDER: E-MEXP-859 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

A new mechanism of SOX9 action to regulate PKCalpha expression in the intestine epithelium.

Dupasquier Sébastien S Abdel-Samad Rana R Glazer Robert I RI Bastide Pauline P Jay Philippe P Joubert Dominique D Cavaillès Vincent V Blache Philippe P Quittau-Prévostel Corinne C

Journal of cell science 20090609 Pt 13

Variations of protein kinase C (PKC) expression greatly influence the proliferation-to-differentiation transition (PDT) of intestinal epithelial cells and might have an important impact on intestinal tumorigenesis. We demonstrate here that the expression of PKCalpha in proliferating intestinal epithelial cells is repressed both in vitro and in vivo by the SOX9 transcription factor. This repression does not require DNA binding of the SOX9 high-mobility group (HMG) domain but is mediated through a ...[more]

PMID: 19509063

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Project description:Vascular calcification and increased extracellular matrix (ECM) stiffness are hallmarks of vascular ageing. Sox9 (SRY-Box Transcription Factor 9) is a master regulator of chondrogenesis, also expressed in the vasculature, that has been implicated in vascular smooth muscle cell (VSMC) osteo-chondrogenic conversion. Here, we investigated the relationship between vascular ageing, calcification and Sox9-driven ECM regulation in VSMCs. Immunohistochemistry in human aortic samples showed that Sox9 was not spatially associated with vascular calcification but correlated with the senescence marker p16. Analysis of Sox9 expression in vitro showed it was mechanosensitive with increased expression and nuclear translocation in senescent cells and on stiff matrices. Manipulation of Sox9 via overexpression and depletion, combined with atomic force microscopy (AFM) and proteomics, revealed that Sox9 regulates ECM stiffness and organisation by orchestrating changes in collagen expression and reducing VSMC contractility, leading to the formation of an ECM that mirrored that of senescent cells. These ECM changes promoted phenotypic modulation of VSMCs whereby senescent cells plated onto ECM synthesized from cells depleted of Sox9 returned to a proliferative state, while proliferating cells on a matrix produced by Sox9 expressing cells showed reduced proliferation and increased DNA damage, reiterating features of senescent cells. Procollagen-lysine, 2-oxoglutarate 5-dioxygenase 3 (LH3) was identified as a Sox9 target, and key regulator of ECM stiffness. LH3 is packaged into extracellular vesicles (EVs) and Sox9 promoted EV secretion, leading to increased LH3 deposition within the ECM. These findings identify cellular senescence and Sox9 as a key regulators of ECM stiffness during VSMC ageing and highlight a crucial role for ECM structure and composition in regulating VSMC phenotype. We identify a positive feedback cycle whereby cellular senescence and increased ECM stiffening promote Sox9 expression which drives further ECM modifications that act to accelerate vascular stiffening and cellular senescence.

Dataset Information

Transcription profiling of human colonic cells before and after induction of the transcription factor SOX9 by doxycycline

Publications

A new mechanism of SOX9 action to regulate PKCalpha expression in the intestine epithelium.

Similar Datasets

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