Background
SOX2 is a key gene implicated in maintaining the stemness of embryonic and adult stem cells. SOX2 appears to re-activate in several human cancers including glioblastoma multiforme (GBM), however, the detailed response program of SOX2 in GBM has not yet been defined.Results
We show that knockdown of the SOX2 gene in LN229 GBM cells reduces cell proliferation and colony formation. We then comprehensively characterize the SOX2 response program by an integrated analysis using several advanced genomic technologies including ChIP-seq, microarray profiling, and microRNA sequencing. Using ChIP-seq technology, we identified 4883 SOX2 binding regions in the GBM cancer genome. SOX2 binding regions contain the consensus sequence wwTGnwTw that occurred 3931 instances in 2312 SOX2 binding regions. Microarray analysis identified 489 genes whose expression altered in response to SOX2 knockdown. Interesting findings include that SOX2 regulates the expression of SOX family proteins SOX1 and SOX18, and that SOX2 down regulates BEX1 (brain expressed X-linked 1) and BEX2 (brain expressed X-linked 2), two genes with tumor suppressor activity in GBM. Using next generation sequencing, we identified 105 precursor microRNAs (corresponding to 95 mature miRNAs) regulated by SOX2, including down regulation of miR-143, -145, -253-5p and miR-452. We also show that miR-145 and SOX2 form a double negative feedback loop in GBM cells, potentially creating a bistable system in GBM cells.Conclusions
We present an integrated dataset of ChIP-seq, expression microarrays and microRNA sequencing representing the SOX2 response program in LN229 GBM cells. The insights gained from our integrated analysis further our understanding of the potential actions of SOX2 in carcinogenesis and serves as a useful resource for the research community. 相似文献Background
Theme-driven cancer survival studies address whether the expression signature of genes related to a biological process can predict patient survival time. Although this should ideally be achieved by testing two separate null hypotheses, current methods treat both hypotheses as one. The first test should assess whether a geneset, independent of its composition, is associated with prognosis (frequently done with a survival test). The second test then verifies whether the theme of the geneset is relevant (usually done with an empirical test that compares the geneset of interest with random genesets). Current methods do not test this second null hypothesis because it has been assumed that the distribution of p-values for random genesets (when tested against the first null hypothesis) is uniform. Here we demonstrate that such an assumption is generally incorrect and consequently, such methods may erroneously associate the biology of a particular geneset with cancer prognosis. 相似文献Gene copy number divergence between species is a form of genetic polymorphism that contributes significantly to both genome size and phenotypic variation. In plants, copy number expansions of single genes were implicated in cultivar- or species-specific tolerance of high levels of soil boron, aluminium or calamine-type heavy metals, respectively. Arabidopsis halleri is a zinc- and cadmium-hyperaccumulating extremophile species capable of growing on heavy-metal contaminated, toxic soils. In contrast, its non-accumulating sister species A. lyrata and the closely related reference model species A. thaliana exhibit merely basal metal tolerance.
ResultsFor a genome-wide assessment of the role of copy number divergence (CND) in lineage-specific environmental adaptation, we conducted cross-species array comparative genome hybridizations of three plant species and developed a global signal scaling procedure to adjust for sequence divergence. In A. halleri, transition metal homeostasis functions are enriched twofold among the genes detected as copy number expanded. Moreover, biotic stress functions including mostly disease Resistance (R) gene-related genes are enriched twofold among genes detected as copy number reduced, when compared to the abundance of these functions among all genes.
ConclusionsOur results provide genome-wide support for a link between evolutionary adaptation and CND in A. halleri as shown previously for Heavy metal ATPase4. Moreover our results support the hypothesis that elemental defences, which result from the hyperaccumulation of toxic metals, allow the reduction of classical defences against biotic stress as a trade-off.
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