Ontology highlight
ABSTRACT:
PROVIDER: PRJEB43594 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| two_deletion_one_missense.vcf.gz | Vcf | |||
| two_deletion_one_missense.vcf.gz.tbi | Vcf |
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Project description:Memory CD8+ T cells are an essential component of protective immunity. Signaling via mechanistic target of rapamycin (mTOR) has been implicated in the regulation of the differentiation of effector and memory T cells. However, little is understood about the mechanisms that control mTOR activity, or the effector pathways regulated by mTOR, in this process. We describe here that tuberous sclerosis 1 (Tsc1), a regulator of mTOR signaling, plays a crucial role in promoting the differentiation and function of memory CD8+ T cells in response to Listeria monocytogenes infection. Mice with specific deletion of Tsc1 in antigen-experienced CD8+ T cells evoked normal effector responses, but were markedly impaired in the generation of memory T cells and their recall responses to antigen re-exposure in a cell-intrinsic manner. Tsc1 deficiency suppressed the generation of memory-precursor effector cells (MPECs) while promoting short-lived effector cell (SLEC) differentiation. Functional genomic analysis indicated that Tsc1 coordinated gene expression programs underlying immune function, transcriptional regulation and cell metabolism. Furthermore, Tsc1 deletion led to excessive mTORC1 activity and dysregulated cellular metabolism including glycolytic and oxidative metabolism. These findings establish a Tsc1-mediated checkpoint in linking immune signaling and cell metabolism to orchestrate memory CD8+ T cell development and function. We used microarrays to explore the gene expression profiles differentially expressed in OVA-specific CD8+ T-cells from wild-type (WT; Tsc1-fl/fl and cre-negative) and Tsc1-/- (Tsc1-fl/fl and Granzyme B-cre-positive) mice
2014-09-20 | E-GEOD-61591 | biostudies-arrayexpress
Project description:The mechanisms that regulate T cell quiescence are poorly understood. We report that tuberous sclerosis complex 1 (Tsc1) establishes a quiescent program in naïve T cells by controlling cell size, cell cycle entry, and responses to T cell receptor stimulation. Loss of quiescence predisposed Tsc1-deficient T cells to apoptosis that depleted conventional T cells and invariant natural killer T cells. Loss of Tsc1 function dampened in vivo immune responses to bacterial infection. Tsc1-deficient T cells exhibited increased mTORC1 but diminished mTORC2 activities, with mTORC1 activation essential for the disruption of immune homeostasis. Therefore, Tsc1-dependent control of mTOR is crucial in establishing naïve T cell quiescence to facilitate adaptive immune function. Naïve CD4 and CD8 T cells from wild-type and Tsc1-deficient mice (in triplicates each group) were stimulated with or without TCR signaling. RNA was analyzed by microarrays. WT/KO for 0 and 4 hr for CD4 (triplicates), and WT/KO for 0 hr for CD8 (duplicates).
2011-07-11 | E-GEOD-29797 | biostudies-arrayexpress
Project description:Chromatin immunoprecipitation DNA-sequencing (ChIP-seq) for CXXC5,CUL4B as well as MTA1 in MCF-7 cells.The pathophysiological function of the CXXC family-member CXXC5 remains to be explored. Here we report that CXXC5 is physically associated with the CRL4B complex and the NuRD complex. Genome-wide investigation of transcriptional targets revealed that the CXXC5/CRL4B/NuRD complex represses a panel of genes including TSC1 that are critically involved in cell growth and the regulation of the mTOR pathway, leading to activation of PD-L1. Intriguingly, CXXC5 expression was increased after stimulation with vitamin B2, whereas vitamin D treatment was accompanied by decreased expression of CXXC5. We demonstrated that the CXXC5-CRL4B-NuRD complex promotes cancer cell proliferation. Elevation of CXXC5, CUL4B, and MTA1 expression during cancer progression corresponded to diminished TSC1 expression, and high levels of CXXC5, CUL4B, and MTA1 strongly correlated with higher histological grades and poor prognosis. We further identified that CXXC5 is bimodally regulated by different kinds of vitamins. Our study revealed that CXXC5-mediated TSC1 suppression activates the mTOR pathway, reduces autophagic cell death, induces PD-L1-mediated immune suppression and results in tumor development, providing a possible mechanistic insight into the pathophysiological function of CXXC5.
2022-12-12 | GSE205362 | GEO
Project description:Tuberous sclerosis complex (TSC), an autosomal dominant disorder caused by mutations in either TSC1 or TSC2, exhibits white matter abnormalities including CNS myelin deficits. however, underlying mechanisms are not fully understood. Here we find that, unexpectedly, constitutive activation of mTOR signaling caused by Tsc1 deletion in the oligodendrocyte lineage results in severe myelination defects and oligodendrocyte cell death. Expression profiling analysis reveals that Tsc1 ablation induces prominent endoplasmic reticulum (ER) stress responses through the PERKâeIF2α dependent signaling axis and activates Fas-JNK apoptotic pathways. Our studies suggest that TSC1-mTOR signaling acts as an important checkpoint for maintaining oligodendrocyte homeostasis. Gene expression profiling of optic nerve from P12 control and Tsc1cKO mice
2016-07-22 | E-GEOD-74893 | biostudies-arrayexpress
Project description:To screen mRNAs specifically regulated by mTORC1, a global mRNA expression profile in calvarial osteoblasts (OBs) from mice with or without OB-specific Tsc1 knockout was developed using microarray. Wild type (WT) or OB-specific Tsc1 knockout (KO) mice were sacrificed, with calvarial osteoblasts harvested and subjected to total RNA extraction.
2015-11-07 | E-GEOD-74781 | biostudies-arrayexpress
Project description:The purpose of this study is to identify the differential transcriptome profiles in WT, hepatic Atg5 KO, TSC1 KO, Atg5/TSC1 DKO, Atg5/TSC1/p62 TKO and Atg5/TSC1/Nrf2 TKO mouse livers. Hepatic mRNA from 2-month-old mice from 5 different mouse strains were extracted and performed for Nextseq analysis in quadruplicates.
2021-12-14 | GSE186783 | GEO
Project description:To screen mRNAs specifically regulated by mTORC1, a global mRNA expression profile in colon epithelial cells (CECs) from mice with or without CECs-specific TSC1 knockout (KO) was developed using microarray. Wile-type or CECs-specific TSC1 KO mice with experimental colitis were sacrificed, with CECs harvested and subjected to total RNA extraction.
2015-11-05 | E-GEOD-74674 | biostudies-arrayexpress
Project description:To identify APA changes in Tsc1-cKO mice, cTag-PAPERCLIP was performed on pAAV-Camk2a-iCre injected Tsc1-WT and Tsc1-floxed cTag-PABP mice. To identify CPSF6-dependent PAS, PAPERCLIP was performed on shCPSF6-BE2C cells with/without doxycycline treatment.
2022-08-11 | GSE210768 | GEO
Project description:Tuberous sclerosis complex (TSC) is an inherited multi-system disorder caused by mutations in the TSC1 or TSC2 gene. TSC patients are often diagnosed with a range of neurodevelopmental (ND) manifestations termed TSC-associated neuropsychiatric disorders (TAND) including autism spectrum disorder (ASD), intellectual disability (ID), anxiety and mood disorders. Hamartin (TSC1) and tuberin (TSC2) proteins form a complex inhibiting mechanistic target of rapamycin complex 1 (mTORC1) kinase signaling. Loss of TSC1 or TSC2 activates mTORC1 that, among several targets, controls protein synthesis by inhibiting translational repressor eIF4E-binding proteins. Using neural progenitor cells (NPCs) from patient-derived induced pluripotent stem cells (iPSCs), we recently reported early ND phenotypic changes, including increased cell proliferation and altered neurite outgrowth in CRISPR-modified TSC1-null NPCs, which were unaffected by mTORC1 inhibition by rapamycin,the only approved therapy for TSC1. Here, to assess TSC1-dependent gene expression programs in NPCs, we used polysome-profiling, which quantifies changes in mRNA abundance and translational efficiencies at a transcriptome-wide level. In addition to changes in mRNA abundance, this revealed numerous TSC1-dependent alterations in translational efficiencies. To assess the relevance of these gene expression alterations we performed polysome-profiling in post-mortem brains originating from ASD donors and matched controls. Strikingly, TSC1-dependent alterations in mRNA translation observed in NPCs were largely recapitulated in human brains. Furthermore, although polysome-profiling revealed a partial reversal of TSC1-associated gene expression alterations following rapamycin treatment, most genes related to neural activity/synaptic regulation or ASD that showed TSC1-dependent translation were rapamycin-insensitive. Therefore, we also examined whether early ND rapamycin-insensitive phenotypes in TSC1-null NPCs could be rescued by a third-generation bi-steric, mTORC1-selective inhibitor RMC-6272 (Revolution Medicines, Inc.). Unlike rapamycin, RMC-6272 strongly inhibited translation and reversed TSC1-associated proliferation and neurite outgrowth phenotypes. In summary, we reveal ample translational alterations in TSC1 patient-derived NPCs recapitulating human brain expression profiles and potential implications for treatment of TAND.
2023-10-27 | GSE239412 | GEO