YAP regulates NFI/KLF5 transcriptional and epigenetic networks directing alveolar epithelial cell differentiation
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA646533 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR12232900_1.fastq.gz | Fastqsanger.gz | |||
| SRR12232900_2.fastq.gz | Fastqsanger.gz | |||
| SRR12232901_1.fastq.gz | Fastqsanger.gz | |||
| SRR12232901_2.fastq.gz | Fastqsanger.gz | |||
| SRR12232902_1.fastq.gz | Fastqsanger.gz |
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Project description:The Nuclear Factor I C (NFI-C) transcription factor has been implicated in TGF-β signaling, extracellular matrix deposition and skin appendage pathologies. We performed a global gene expression analysis in NFI-C-/- and wild-type embryonic primary murine fibroblasts. This indicated that NFI-C acts mostly to repress gene expression in response to TGF-β1. Misregulated genes featured a prominent over-representation of regulators of connective tissue inflammation and repair.
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Project description:Activation of the Ras/Erk pathway upregulates expression of the Kruppel-like Factor 5 (KLF5) transcription factor, and KLF5 is a downstream mediator of Ras oncogenic signaling. Specifically, in bladder and colon cancer cell lines KLF5 upregulates the Ras-pathway target gene cyclin D1, and facilitates entry into the S phase of the cell cycle. Ras mutations are common in lung cancer, but a role for KLF5 in lung tumorigenesis has not been defined. To this end, we manipulated KLF5 expression in four Ras-mutant human lung adenocarcinoma cell lines to find that KLF5 significantly modulates anchorage-independent growth, a mutant Ras phenotype. However, in a mouse model of human lung adenocarcinoma, K-RasG12D does not critically require Klf5 to mediate oncogenesis or induce cyclin D1 expression. Patients with lung tumors expressing high levels of KLF5 have significantly better prognosis than those with low or no KLF5 expression (opposite of mutant Ras prognosis). The latter may be explained by KLF5 transcriptional repression of the ATP-binding cassette, sub-family G (WHITE), member 2 (ABCG2), an anthracycline transporter. In agreement with this, KLF5 knockdown cells display significantly more Hoechst “side population” and resistance to doxorubicin. In summary, while KLF5 is not an obligate partner in Ras oncogenic signaling, KLF5 control of ABCG2 expression is significant to patient survival.
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Project description:The conserved Nuclear Factor I (NFI) family of transcription factors is unique to animals and essential for mammalian development. The C. elegans genome encodes a single NFI family member, whereas vertebrate genomes encode four distinct NFI protein subtypes (A, B, C, and X). NFI-1 deficient worms exhibit abnormalities including reduced lifespan, defects in movement and pharyngeal pumping, and delayed egg-laying. To explore the functional basis of these phenotypes, we sought to comprehensively identify NFI-1 binding targets in C. elegans. We first established NFI-1 DNA-binding specificity using an in vitro DNA-selection strategy. Analysis yielded a consensus motif of TTGGCA(N3)TGCCAA, which occurs 586 times in the genome, a 100-fold higher frequency than expected. We next asked which sites were occupied by NFI-1 in vivo by performing chromatin immunoprecipitation of NFI-1 followed by microarray hybridization (ChIP-chip). Only 55 genomic locations were identified, an unexpectedly small target set. In vivo NFI-1 binding sites tend to be upstream of genes involved in core cellular processes such as chromatin remodeling, mRNA splicing, and translation. Remarkably, 67/80 (84%) of the C. briggsae homologs of the identified targets contain conserved NFI binding sites in their promoters. These experiments provide a foundation for understanding how NFI-1 is recruited to unexpectedly few in vivo sites to perform its developmental functions, despite a vast over-representation of its binding site. To our knowledge, this represents the first genome-wide location study of any transcription factor in C. elegans, and the first genome-wide analysis in any species of an NFI transcription factor. 4 biological replicates of NFI-1 ChIP-chip (including 1 dye-swap) were performed with 2 pre-immune Mock ChIP-chip controls from corresponding extracts.
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