K-RAS activating mutations occur frequently in non-small cell lung cancer (NSCLC), leading to aberrant activation of Ras-MAPK signaling pathway that contributes to the malignant phenotype. However, the development of Ras-targeted therapeutics remains challenging. Here, we show that MED23, a component of the multisubunit Mediator complex that is known to integrate signaling and gene activities, is selectively important for Ras-active lung cancer. By screening a large panel of human lung cancer cell lines with or without a Ras mutation, we found that Med23 RNAi specifically inhibits the proliferation and tumorigenicity of lung cancer cells with hyperactive Ras activity. Med23-deficiency in fibroblasts selectively inhibited the oncogenic transformation induced by Ras but not by c-Myc. Transcription factor ELK1, which is phosphorylated by MAPK for relaying the Ras signaling to MED23, was also required for the Ras-driven oncogenesis. Transcriptiome analysis revealed that MED23 and ELK1 co-regulate a common set of target genes enriched in regulating cell cycle and proliferation to support the Ras-dependency. Furthermore, correlated with the strength of Ras signaling as indicated by the ELK1 phosphorylation level, MED23 was up-regulated by Ras-transformation, and was found to be overexpressed in both Ras-mutated lung cancer cell lines and primary tumor samples. Remarkably, lower Med23 expression predicts better survival in Ras-active lung cancer patients and xenograft mice. Collectively, our findings demonstrate a critical role for MED23 in enabling the Ras-addiction of lung carcinogenesis, thus providing a vulnerable target for the treatment of Ras-active lung cancer.
Selective requirement for Mediator MED23 in Ras-active lung cancer.
Specimen part, Cell line
View SamplesHistone methylation is a complex posttranslational modification regulating transcription and chromatin dynamics, and plays important roles in development and disease processes. Recent studies indicate that histone lysine methylation is a reversible modification and several JmjC-domain-containing proteins have been identified as histone lysine demethylases. Here we show that KIAA1718, a JmjC-domain-containing protein, is a histone demethylase. KIAA1718 demethylated dimethylation of H3 lysine 9 and 27 (H3K9me2 and H3K27me2), two important epigenetic marks associated with embryonic development6-10. In mouse embryonic stem cells (ESCs), KIAA1718 expression increased at the early phase of neural differentiation. RNA interference inhibition of KIAA1718 blocked neural differentiation and the effect was rescued by wild-type human gene, but not by a catalytically inactive mutant. In chick embryos, KIAA1718 is exclusively expressed in the epiblast cells of the primitive streak, an organizer contributing to neural induction. Knockdown of KIAA1718 resulted in defects in neural formation, while its overexpression led to neural expansion. The pro-neural effect is mediated through transcriptional activation of FGF4, a growth factor implicated in neural induction. Thus, our study identifies a dual specific histone demethylase as a novel epigenetic factor integrated with growth factor signaling, which has important roles in the early neural development.
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Specimen part, Cell line
View SamplesCompare the gene expression profiles of ESCs stably expressing control and KIAA1718 short hairpin RNA, using Affymetrix microarray.
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Specimen part, Cell line
View SamplesWe reasoned that the pi-RISC, by virtue of the enormous sequence portfolio of piRNAs, might mediate elimination of a large variety of mRNAs in late stages of spermiogenesis. Both Miwi-null and Caf1-null mice showed early spermiogenic arrest, preventing us from determining the role of MIWI and CAF1 in elongating spermatids using the existing genetic models.
Pachytene piRNAs instruct massive mRNA elimination during late spermiogenesis.
Specimen part
View SamplesZygotic genome activation (ZGA), which is according to the midblastula transition in zebrafish, is an important event during the maternal-zygotic transition in animals. Our preliminary study and other groups works indicate that epigenetic regulations play an essential role in ZGA.
Protein Arginine Methyltransferase 6 (Prmt6) Is Essential for Early Zebrafish Development through the Direct Suppression of gadd45αa Stress Sensor Gene.
Age, Specimen part
View SamplesDCs treated with PTX (PTX-DC) is able to induce EAE like PTX as adjuvant whereas neither LPS nor DCs treated with LPS (LPS-DC) fails to induce EAE. We want to identify genes that are responsible for EAE induction in DCs and genes that are able to toloerize EAE in DCs through the microarray.
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Specimen part, Treatment
View SamplesRNA-Seq experiment was done to compare cngc16 (a heat-sensitive mutant harboring a knockout of cyclic nucleotide-gated channel 16) and wild type pollen for differences in their response to a temperature stress condition. Transcriptomes were analyzed from mature pollen grains harvested at midday from plants grown under normal (control) conditions or a heat stress regime. For the stress condition, plants were grown under a diurnal cycle of hot and cold temperatures and pollen were harvested at the end of a HS period that peaked at 40 degrees Celsius.
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Specimen part, Treatment
View SamplesExosomes are 40~120 nm diameter vesicles of endocytic origin released by most cells and important in mediating cell-cell communication. As mRNA and noncoding RNA are two main functional RNA molecules in post transcription level and involves in many bio-activities including cancer progression and metastasis, it is important to understand the coding and noncoding genes contained within exosomes released by tumour cells. This study focused on the protein coding and noncoding genes enriched in two subtypes of exosomes (A33-enriched exosomes, A33-Exos and EpCAM-enriched exosomes, EpCAM-Exos) released by human colon cancer LIM1863 cell line. With high throughput sequencing technology and bioinformatics analyses, we demonstrate 350 protein coding genes (PCGs) and 222 noncoding genes (NCGs) are commonly enriched; 56 PCGs and 202 NCGs were specifically enriched in A33-Exos and 276 PCGs and 253 NCGs were enriched unique to EpCAM-Exos. A salient finding was the significant enrichment of TPT1, ribosomal protein genes and GAS5, a tumour noncoding gene, in exosomes. We further demonstrate differentially seven expressed genes (SCARB1, SCD, TPT1, EETF1G, BCL7C, RPS3, and RAB13) by qRT-PCR. Importantly, we correlated these findings with several matched tissue-derived tumour-normal samples showed TPT1 and ribosomal protein genes were up regulated in human tumour samples. Our findings provide a new insight of functional RNA molecules in exosomes and new select non-invasive biomarker candidates for colon cancer diagnosis and prognosis.
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No sample metadata fields
View SamplesTranscriptional response to plant extract
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Sex, Specimen part, Cell line, Treatment
View SamplesStudies in human innate lymphoid cell (ILC) development are important in understanding the pathophysiology of immune deficiencies and providing insights into the design of immunotherapies for patients with cancer, infection, and autoimmune disease. Currently, it is unclear where and how ILCs develop in humans. The overall goal of our study is to gain a comprehensive understanding of the cellular and molecular components that regulate human ILC development and function in order to best understand how they work in physiological and pathological states.
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