Transcriptome analysis of TSC1 and TSC2 using Nanopore long-read sequencer
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1008094 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR25737012_1.fastq.gz | Fastqsanger.gz | |||
| SRR25737013_1.fastq.gz | Fastqsanger.gz | |||
| SRR25737014_1.fastq.gz | Fastqsanger.gz |
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Project description:Tuberous sclerosis complex (TSC) is a relatively common autosomal dominant disorder characterized by multiple dysplastic organ lesions and neuropsychiatric symptoms, caused by loss-of-function mutation of either TSC1 or TSC2. Target-capture full-length double-stranded cDNA sequencing using long-read sequencer Nanopore (Nanopore Long-read Target Sequencing) revealed that the various kinds of the TSC1 and TSC2 full-length transcripts and the novel intron retention transcripts of TSC2 in TSC patient. Our results indicate that the Nanopore Long-read Target Sequencing is useful for the detection of mutations and confers information on the full-length alternative splicing transcripts for the genetic diagnosis.
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Project description:The tuberous sclerosis complex (TSC) family of tumor suppressors, TSC1 and TSC2, function together in an evolutionarily conserved protein complex that is a point of convergence for major cell signaling pathways that regulate mTOR complex 1 (mTORC1). Mutation or aberrant inhibition of the TSC complex is common in various human tumor syndromes and cancers. The discovery of novel therapeutic strategies to selectively target cells with functional loss of this complex is therefore of substantial clinical relevance to TSC and sporadic cancers. We developed a CRISPR-based method to generate homogenous mutant Drosophila cell lines. By combining TSC1 and TSC2 mutant cell lines with RNAi screens against all kinases and phosphatases, we identified synthetic interactions with TSC1 and TSC2. Knockdown of three candidate genes (mRNA-cap, Pitslre and CycT; orthologs of RNGTT, CDK11 and CCNT1 in humans) reduced the population growth rate of both Drosophila TSC1 and TSC2 mutant cells but not that of wild-type cells. Moreover, knockdown of all three genes displayed similar selective effects in mammalian TSC2-deficient cell lines, including human tumor-derived cells, illustrating the power of this cross species screening strategy to identify potential drug targets.
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Project description:Metabolic fitness of T cells is crucial for immune responses against infections and tumorigenesis. Both the T cell receptor (TCR) signal and environmental cues contribute to the induction of T cell metabolic reprogramming, but the underlying mechanism is incompletely understood. Here we identified the E3 ubiquitin ligase Peli1 as an important regulator of T cell metabolism and antitumor immunity. Peli1 ablation profoundly promotes tumor rejection, associated with increased tumor-infiltrating CD4 and CD8 T cells. The Peli1-deficient T cells display markedly stronger metabolic activities, particularly glycolysis, than wildtype T cells. Peli1 controls the activation of a metabolic kinase, mTORC1, stimulated by both the TCR signal and growth factors, and this function of Peli1 is mediated through regulation of the mTORC1-inhibitory proteins, TSC1 and TSC2. Peli1 mediates non-degradative ubiquitination of TSC1, thereby promoting TSC1-TSC2 dimerization and TSC2 stabilization. These results establish Peli1 as an important regulator of T cell metabolism and antitumor immunity and suggest a novel mechanism that controls mTORC1 activation.
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Project description:Rationale: Increased matrix metalloproteinase (MMP) activity has been implicated in the pathogenesis of lymphangioleiomyomatosis (LAM). Objectives: To investigate how TSC1 or TSC2 deficiency alters MMP expression and regulation. Methods: We studied immortalized cells that lack TSC2 derived from an angiomyolipoma (AML) of a LAM patient, and a TSC2 add back derivative; and murine embryonic fibroblast cells that lack Tsc1 or Tsc2 and respective controls. Global gene expression analysis was carried out in the AML and derivative cell lines. MMP levels in the conditioned media from these cells were analyzed by zymography and ELISA. Measurements and Main Results: We found increased MMP-2 expression in cells lacking TSC1/TSC2 compared to their respective controls by zymography. MMP-2 overproduction by these cells was not affected by rapamycin treatment. Gene expression analysis confirmed increased MMP-2 gene expression that was not affected by rapamycin. Furthermore, multiple other genes were found to be over-expressed in rapamycin-treated TSC2-deficient cells compared to TSC2+ cells. Conclusions: We conclude that TSC1/TSC2 deficiency leads to MMP-2 overproduction that is rapamycin insensitive, and that several genes exhibit similar patterns suggesting TSC1/TSC2 dependent but mTOR independent pathways may be involved in the pathogenesis of LAM.
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Project description:HSP90 and its co-chaperon R2TP are involved to assemble and stabilize many macro-molecular complexes involved in cell proliferation. R2TP complex is composed of RUVBL1 and RUVBL2 AAA+ ATPases and two adapter proteins RPAP3 and PIH1D1. The N-terminal domain of PIH1D1 was described to possess a basic pocket that binds phosphorylated peptides on some of the R2TP clients. Subunits of TSC complex (Tuberous SClerosis) have previously been described in proteomic analysis of proteins immune-precipitated with PIH1D1 N-terminal domain. TSC complex is a regulator of mTOR activity. It is composed of TSC1, TSC2 and TBC1D7 subunits. Here, we show that (i) TSC1 and TSC2 are both substrates of HSP90, (ii) the HSP90/R2TP system has multiple interaction with TSC complex subunits and (iii) it is functionally involved in the assembly of the TSC complex. We found a direct interaction of TSC1 with the phospho-binding pocket of PIH1D1 N-terminal domain regardless of phosphorylationbut in a non-canonical phosphorylation independent manner[XM1] . TSC2 and TBC1D7 would also interact with R2TP but independently of PIH1D1. Taken together, these data suggest that R2TP acts as a platform for the independent recruitment of TSC subunits before the assembly of the TSC complex
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