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METTL3 governs thymocyte development and thymic involution by regulating ferroptosis

ABSTRACT: METTL3 governs thymocyte development and thymic involution by regulating ferroptosis

PROVIDER: PRJNA1130936 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR29682400_1.fastq.gz	Fastqsanger.gz
	SRR29682400_2.fastq.gz	Fastqsanger.gz
	SRR29682401_1.fastq.gz	Fastqsanger.gz
	SRR29682401_2.fastq.gz	Fastqsanger.gz
	SRR29682402_1.fastq.gz	Fastqsanger.gz

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METTL3 governs thymocyte development and thymic involution by regulating ferroptosis

Project description:Given its central role in immune aging, identifying regulators of thymic involution is important. While conventional programmed cell death plays a fundamental role in thymocyte development, how cell death pathways contribute to thymic involution remains unclear. In this study, we found that CD4+CD8+ double positive (DP) thymocytes acquired characteristics of senescence in aged mice undergoing thymic involution, while expression of the m6A methyltransferase METTL3 (enriched in DP cells from young mice) decreased with aging. By conditionally deleting METTL3 in T cells, we revealed a critical role for METTL3 in DP cell survival, and in restraining features of aging in DP thymocytes by preventing ferroptosis signaling, through glutathione peroxidase 4 (GPX4). Mechanistically, GPX4 was maintained by METTL3 at the translational level, independent of its methyltransferase activity. Furthermore, we found that pharmacological inhibition of ferroptosis promoted DP cell survival, and attenuate d features of aging in DP thymocytes. These findings uncover a role for METTL3-regulated ferroptosis in thymic involution, and identify strategies to restore thymic function.

2024-08-18 | GSE271324 | GEO

Notch-Induced Endoplasmic Reticulum-Associated Degradation Governs Thymocyte β Selection

Project description:Notch-Induced Endoplasmic Reticulum-Associated Degradation Governs Thymocyte β Selection

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Notch-Induced Endoplasmic Reticulum-Associated Degradation Governs Thymocyte β Selection

Project description:β -selection imposes a considerable demand for new protein synthesis of the newly rearranged Tcrβ gene and the multiple factors that execute the transcriptional and metabolic programs demanded by DN thymocyte proliferation. However, how proteome homeostasis or “proteostasis” is regulated during thymocyte development is largely unknown. Here, we show that the endoplasmic reticulum (ER)- associated degradation (ERAD), but not the unfolded protein response (UPR), is the master regulator of physiological ER proteostasis in immature DN thymocytes. The ERAD machinery was critically required for successful β-selection of DN3 thymocytes and consequently, ERAD deficiency impeded αβ T cell development. The Sel1L-Hrd1 complex is the most conserved branch of mammalian ERAD machinery. Deletion of Sel1l impaired DN3 to DN4 thymocyte transition and severely impaired αβ T cell development. Mechanistically, Sel1l deficiency induced unresolved ER stress that triggered thymocyte apoptosis through the PERK pathway. This study revealed the stringent protein quality control through the SEL1L-ERAD pathway is required for successful b-selection and the development of the ab T cells that mediate adaptive immunity.

2021-05-07 | GSE173993 | GEO

Global transcriptional profiling reveals distinct functions of thymic stromal subsets and age-related changes during thymic involution

2014-09-12 | GSE56928 | GEO

Global transcriptional profiling reveals distinct functions of thymic stromal subsets and age-related changes during thymic involution

Project description:The thymic microenvironment is essential for proper differentiation and selection of thymocytes.Thymic involution in aged mice results in decreased T cell output and immune function. Here we use gene expression profiling of FACS sorted thymic stromal subsets to identify molecular mediators of thymocyte: stromal cell interactions, as well as gene expression changes thymic stromal subsets during early stages of thymic involution . We used microarrays to analyze gene expression differences between thymic stromal subsets from male C57BL/6J mice 1, 3, and 6 months of age. Thymic stromal subsets (cTEC, mTEClo, mTEChi, Sirpa-DC, Sirpa+DC, and fibroblasts) were isolated from two 1-, 3-, and 6- month old male C57BL/6J mice. After enzymatic digestion of the thymi, the stromal cells were FACS purified, and RNA was extracted, amplified, labeled and hybridized to Affymetrix mouse 430 2.0 arraysarrays. Raw data were uploaded to Gene Expression Commons for normalization. Both raw CEL and normalized datasets from the 36 samples are included. A model within Gene Expression Commons has been created for analyses/comparisons of these datasets, along with previously reported thymocyte subset datasets. The model within Gene Expression Commons thus contains 6 thymic stromal populations, each from mice 1, 3, and 6 months of age, with duplicates for each datset.

2014-09-12 | E-GEOD-56928 | biostudies-arrayexpress

Role of AhR in thymocyte emigration in vivo

2008-11-25 | GSE10166 | GEO

Role of AhR in thymocyte emigration in vivo

Project description:Over-activation of the aryl hydrocarbon receptor by TCDD in mice leads among other phenotypes to a severe thymic atrophy accompanied by immunosuppression. TCDD causes a block in thymocyte maturation and a preferential emigration of immature CD4-CD8- DN thymocytes (recent thymic emigrants) into the periphery. As part of this study gene expression profiles from DN thymocytes and thymic emigrants were generated from TCDD and solvent control mice Keywords: Affymetrix, TCDD, CD4-CD8- thymocytes, Thymus involution, thymic emigration, Ahr Female, 6-8 week old C57BL6 mice were i.p. injected with 10 M-BM-5g/kg TCDD. After 5 days mice were anesthezised and FITC injected into their thymi. after 24h mice were sacrificed and CD4-CD8-FITC+ cells isolated from thymus (thymocytes) and spleen (recent thymus emigrants).

2008-11-25 | E-GEOD-10166 | biostudies-arrayexpress

Lysosomal cystine governs ferroptosis sensitivity in cancer via nuclear cysteine response

Project description:Lysosomal cystine governs ferroptosis sensitivity in cancer via nuclear cysteine response

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METTL3 promotes translation in human cancer cells

Project description:we find METTL3 associates with polyribosomes and promotes translation. METTL3 depletion inhibits translation, and both wild-type and catalytically inactive METTL3 promote translation when tethered to the 3' untranslated region (UTR) of a reporter mRNA. Mechanistically, METTL3 enhances mRNA translation through an interaction with the translation initiation machinery. m6A seq in A549 and H1299 cells, RNA seq in METTL3 knockdown cells

2016-07-03 | E-GEOD-76367 | biostudies-arrayexpress

METTL3 KD in HepG2 cells

Project description:To gain insight into possible processes that require m6A for their function, METTL3 was knocked down (KD) in HepG2 cells by siRNA transfections Differential expression analysis of METTL3 KD versus mock-transfected HepG2 cells, in 2 biological replicates

2012-04-25 | E-GEOD-37001 | biostudies-arrayexpress

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