Transcriptomics,Genomics

Dataset Information

156

Convergent roles of ATF3 and CSL in chromatin control of CAF activation [RNA-seq]


ABSTRACT: Cancer associated fibroblasts (CAFs) play an important role in initiating and promoting epithelial cancers. The specific chromatin modifications involved in CAF activation remain to be elucidated. CSL, a constitutive transcriptional repressor and mediator of canonical Notch signaling, functions as a direct negative regulator of CAF effector genes and suppresses cancer/stromal cell expansion. We find that ATF3, a key stress responsive transcriptional repressor up-regulated in the acute UVA response of skin fibroblasts, is down-modulated in stromal cells of premalignant skin SCC lesions similarly to CSL. Increased ATF3 expression counteracts the consequences of compromised CSL, binding to a large set of overlapping target genes. At low basal levels, ATF3 converges with CSL in negative control of CAF activation, binding to a very small number of genomic loci that encompass mostly non-coding RNAs and pseudogenes. Silencing of ATF3 results in chromatin modifications and Pol II recruitment to many loci to which ATF3 does not bind, which are similarly affected by CSL silencing. The observed changes are of functional significance, as Bet inhibitors, which unlink activated chromatin from the basic transcription apparatus, have opposite effects of ATF3 or CSL silencing on all tested CAF effector genes. They exert a similar impact on clinically-derived CAFs both in vitro and upon topical in vivo treatment. Thus, ATF3 converges with CSL in global chromatin control of CAF activation with their loss eliciting epigenetic changes amenable to cancer and stroma-focused intervention. Overall design: Human Dermal Fibroblasts were infected with pInd-ATF3 viruses and treated for 3 days with doxyciclin at two different doses (100 and 500 ng/ml) in parallel with vehicle for 3 days, followed by RNA-Seq analysis. Human Dermal Fibroblasts were transfected with two different siRNA against ATF3 in parallel with a control siRNA. Total RNA was extracted 3 days post-transfection, followed by RNA-Seq analysis (DEK32-37). Cancer Associated Fibroblasts were treated with JQ1 (500nM) or vehicle (DMSO) for 48 hours, followed by RNA-Seq analysis (DMSO_1-3, JX_1-3).

INSTRUMENT(S): Illumina HiSeq 2500 (Homo sapiens)

SUBMITTER: Paolo Angelino  

PROVIDER: GSE81405 | GEO | 2017-06-30

SECONDARY ACCESSION(S): PRJNA321476

REPOSITORIES: GEO

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Publications

Convergent roles of ATF3 and CSL in chromatin control of cancer-associated fibroblast activation.

Kim Dong Eun DE   Procopio Maria-Giuseppina MG   Ghosh Soumitra S   Jo Seung-Hee SH   Goruppi Sandro S   Magliozzi Francesco F   Bordignon Pino P   Neel Victor V   Angelino Paolo P   Dotto G Paolo GP  

The Journal of experimental medicine 20170706 8


Cancer-associated fibroblasts (CAFs) are important for tumor initiation and promotion. CSL, a transcriptional repressor and Notch mediator, suppresses CAF activation. Like CSL, ATF3, a stress-responsive transcriptional repressor, is down-modulated in skin cancer stromal cells, and Atf3 knockout mice develop aggressive chemically induced skin tumors with enhanced CAF activation. Even at low basal levels, ATF3 converges with CSL in global chromatin control, binding to few genomic sites at a large  ...[more]

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