ATF3 drives senescence by reconstructing accessible chromatin profiles
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA663096 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR12628585_1.fastq.gz | Fastqsanger.gz | |||
| SRR12628585_2.fastq.gz | Fastqsanger.gz | |||
| SRR12628586_1.fastq.gz | Fastqsanger.gz | |||
| SRR12628586_2.fastq.gz | Fastqsanger.gz | |||
| SRR12628587_1.fastq.gz | Fastqsanger.gz |
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Project description:Here we describe the transcriptional response to Atf3 expression in the EAD. Atf3 is a cell polarity response gene acting downstream of the membrane-associated Scribble polarity complex. Loss of the neoplastic tumor suppressors Scribble or Dlg1 induces Atf3 expression via aPKC signaling. Using ChIP-seq we have determined that Atf3 targets are enriched for roles in cytoarchitecture. Gain of Atf3 function interferes with organization of the microtubule network, thereby disturbing vesicular trafficking processes including endocytosis, and consequently alters the distribution of key polarity proteins along the apicobasal axis. Conversely, removal of Atf3 from cells lacking Dlg1 suppresses trafficking defects and restores both the normal localization of polarity determinants and epithelial differentiation. These results thus establish loss of polarity as a novel cue that induces Atf3 and demonstrate that gain of Atf3 function drives specific hallmarks of epithelial cells deficient for the Scribble polarity module.
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Project description:Cancer-host interactions play an important role in cancer development. We identified ATF3, an adaptive-response gene, in the host to facilitate metastasis. We also demonstrated that the macrophage is one of the key cell types for host-ATF3 to function. Furthermore, matrix metalloproteases 9 is a functionally important target gene of ATF3 in co-culture assays. Gene profiling with bioinformatics analyses indicated that ATF3 downstream gene-signatures derived from tumor-associated macrophages in a mouse model can distinguish human tumor stroma from M-bM-^@M-^\distantM-bM-^@M-^] stroma in and can stratify the patients into high- versus low-risk groups. Importantly, multivariate analyses indicated that high expression of ATF3 itself in mononuclear cells within breast tumors is an independent predictor for breast cancer-specific death in a cohort of patients. Approximately 21 days after orthotopic injection of PyMT breast cancer cells into syngeneic C57BL/6 mice (WT or ATF3 KO hosts) tumors were removed (tumors were ~1 cm cubic in volume), enzymatically digested to generate single cell suspensions, stained, and sorted for F4/80 and CD45 double positive cells by FACS. Isolated cells were lysed in TRIzol, processed to generate total RNA, and gene expression analyzed by microarray. Four replicate WT TAM samples and four replicate ATF3 KO TAM samples were analyzed.
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Project description:Maintenance of genetic integrity is essential for survival of all organisms. Activating transcription factor 3 (ATF3) is a member of the c-AMP response element binding (CREB)/ATF family of transcription factors, and is highly inducible by various stress conditions including DNA damage. However, downstream targets and molecular basis underlying pleiotropic effects of ATF3 on the cell fate have been largely unknown. To identify ATF3 targets in the human genome, we carried out chromatin immunoprecipitation-microarray (ChiP-on-chip) and knockdown-expression profiling analysis using two models where ATF3 was either transiently induced or constitutively expressed. We show that ATF3 binds to an unexpectedly large number of targets; 5,984 promoters in HCT116 cells treated with an alkylating agene methyl methanesulfonate (MMS) and 1,423 promoters in LNCaP cells constitutively expressing ATF3. Importantly, targets of MMS-induced ATF3 are highly enriched not only for CREB/ATF motifs but also for binding sites of several stress sensors including DDIT3/CHOP, Egr1, and c-Ets which are concomitantly induced by MMS. Stress-induced ATF3 affects broad but select biological processes including cell cycle, cell death, adhesion, biosynthesis, and receptor signaling pathways. In addition, ATF3 binds to as many as 40% of the p53 targets and preferentially enhances MMS-induced activation of proapoptotic genes such as DR4, DR5, and PUMA, consistent with the proapoptotic effect of ATF3. These data shed new light on the co-regulatory function of ATF3 in the stress-induced transcription factor network. The comprehensive list of genomic targets of ATF3 will facilitate further understanding the role of ATF3 in determining life and death of cells under both physiological and tumour-associated stress conditions. Maintenance of genetic integrity is fundamental to survival of all organisms. DNA damage can be caused by various agents in environment and elicits complex responses in the cell. ATF3 is one of the transcription factors activated by various stress conditions including DNA damage, and has been shown to have pleiotropic effects on life and death of cells depending on the context of experimental conditions. It has been largely unknown, however, which genes and pathways are regulated by stress-induced ATF3. Here we attempted to answer this question by chromatin immunoprecipitation-microarray analysis of downstream targets of ATF3. We show that ATF3 binds to an unexpectedly large number of promoters (nearly 6,000) in a human colorectal cancer cell lineHCT116 treated with an alkylating agent methyl methanesulfonate. Interestingly, the ATF3 targets are highly enriched for binding sites of other stress sensors shedding light on a transcriptional co-regulatory network of DNA damage response. We further show that ATF3 regulates expression of genes in select biological processes including cell cycle, cell death, adhesion, metabolism, signal transduction, and the p53 pathway. The comprehensive list of ATF3 targets provides new insight into a highly inter-connected network of stress-induced transcription factors around ATF3. ChIP-chip samples: Comparison of ATF3-IP and whole genome DNA (control) Gene expression samples: HCT116 cells pre-transfected with either control siRNA or ATF3 knockdown siRNA and stimulated by methyl methanesulfonate (MMS) for 0, 6, 12, and 24 hours
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