METTL3 dictates the development of thymocytes via restraining ferroptosis program during age related thymic involution
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ABSTRACT:
PROVIDER: PRJNA1017361 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR26059332_1.fastq.gz | Fastqsanger.gz | |||
| SRR26059332_2.fastq.gz | Fastqsanger.gz | |||
| SRR26059333_1.fastq.gz | Fastqsanger.gz | |||
| SRR26059333_2.fastq.gz | Fastqsanger.gz | |||
| SRR26059334_1.fastq.gz | Fastqsanger.gz |
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Project description:Thymic involution is a crucial factor in immune system aging and results in age-related impairment of T cell responses. The control of programmed cell death plays a fundamental role in thymocytes development. How thymocytes cell death contribute to thymic involution remains elusive. In this study, we found that METTL3 is highly expressed in double positive (DP) cells from young mice but decreased in aged mice. Mice conditionally deficiency for METTL3 in T cells showed thymic involution phenotypes with decreased survival and increased senescent DP cells. Additionally, METTL3 deficiency elicited ferroptosis program rather than other cell death pathways and led to defective DP cell development. Furthermore, GPX4, a molecule that protects cells from ferroptosis, was essential for thymocyte survival and preventing senescence. Mechanistically, GPX4 was maintained by METTL3 at the translation level in METTL3 methyltransferase activity independent manner. Targeting METTL3 and ferroptosis process promoted DP cell survival and reinvigorated aged DP cells. These findings reveal the central role of the METTL3-GPX4-ferroptosis axis in regulating thymocyte homeostasis and identifying targets for impeding age-related thymic involution and diseases.
2025-03-01 | GSE243187 | GEO
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
Project description:The thymus is the site of T lymphocyte development and T cell education to recognize foreign, but not self, antigens. B cells also reside and develop in the thymus, although their function(s) are less clear. During ‘thymic involution,’ a process of lymphoid atrophy and adipose replacement linked to sexual maturation, thymic cells decline. However, thymic B cells decrease far less than T cells, such that B cells comprise ~1% of neonatal thymocytes, but up to ~10% in adulthood in humans. All jawed vertebrates possess a thymus, and we and others have shown that zebrafish (Danio rerio) also have thymic B cells. Here, we investigated the precise identities of zebrafish thymic T and B cells and how they change with involution. We assessed the timing and specific details of zebrafish thymic involution using multiple lymphocyte-specific, fluorophore-labeled transgenic lines, quantifying changes in thymic lymphocytes pre- vs. post-involution. Our results prove that, as in humans, zebrafish thymic B cells increase relative to T cells post-involution. We also performed RNA sequencing (RNA-seq) on D. rerio thymic and marrow lymphocytes of four novel double-transgenic lines, identifying distinct populations of immature T and B cells. Collectively, this is the first comprehensive analysis of zebrafish thymic involution, demonstrating its similarity to human involution, and establishing the highly genetically-manipulatable zebrafish model as a template for involution studies.
2024-04-02 | GSE237139 | GEO
Project description:METTL3 governs thymocyte development and thymic involution by regulating ferroptosis
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Project description:The decline in adaptive immunity, naïve T-cell output and a contraction in the peripheral T cell receptor (TCR) repertoire with age are largely attributable to thymic involution and the loss of critical cytokines and hormones within the thymic microenvironment. To assess the molecular changes associated with this loss of thymic function, we used cDNA microarray analyses to examine the transcriptomes of thymocytes from mice of various ages ranging from very young (1 month) to very old (24 months). Genes associated with various biological and molecular processes including oxidative phosphorylation, T- and B- cell receptor signaling and antigen presentation were observed to significantly change with thymocyte age. These include several immunoglobulin chains, chemokine and ribosomal proteins, annexin A2, vav 1 and several S100 signaling proteins. The increased expression of immunoglobulin genes in aged thymocytes could be attributed to the thymic B cells which were found to be actively producing IgG and IgM antibodies. Upon further examination, we found that purified thymic T cells derived from aged but not young thymi also exhibited IgM on their cell surface suggesting the possible presence of auto-antibodies on the surface thymocytes with advancing age. These studies provide valuable insight into the cellular and molecular mechanisms associated with thymic aging. Keywords: Thymocytes, thymic involution, aging, time course
2009-05-05 | GSE15945 | GEO
Project description:The decline in adaptive immunity, naïve T-cell output and a contraction in the peripheral T cell receptor (TCR) repertoire with age are largely attributable to thymic involution and the loss of critical cytokines and hormones within the thymic microenvironment. To assess the molecular changes associated with this loss of thymic function, we used cDNA microarray analyses to examine the transcriptomes of thymocytes from mice of various ages ranging from very young (1 month) to very old (24 months). Genes associated with various biological and molecular processes including oxidative phosphorylation, T- and B- cell receptor signaling and antigen presentation were observed to significantly change with thymocyte age. These include several immunoglobulin chains, chemokine and ribosomal proteins, annexin A2, vav 1 and several S100 signaling proteins. The increased expression of immunoglobulin genes in aged thymocytes could be attributed to the thymic B cells which were found to be actively producing IgG and IgM antibodies. Upon further examination, we found that purified thymic T cells derived from aged but not young thymi also exhibited IgM on their cell surface suggesting the possible presence of auto-antibodies on the surface thymocytes with advancing age. These studies provide valuable insight into the cellular and molecular mechanisms associated with thymic aging. Keywords: Thymocytes, thymic involution, aging, time course 3 replicates each from the 6, 16 and 24 month old animals were labeled with Cy-3 and hybridized with a Cy-5 labeled pool from 1 month old mice. The data from the 2 channels are being reported here separately.
2009-05-05 | E-GEOD-15945 | biostudies-arrayexpress
Project description:The thymus is a primary lymphoid organ generating self-restricted and self-tolerant naïve T-cells. Early in life the thymus starts to involute, resulting in decreased naïve T-cell output which may be more self-reactive, leading to an increased prevalence of autoimmunity. A decrease in the transcription factor FOXN1 is an early event in thymic involution. Using the Foxn1lacz model, we studied how premature thymic involution affects the thymic microenvironment, thymocytes, and peripheral T cell immunity. We found that early thymic involution led to aged-like thymic epithelial cells that resulted in aged-like thymocyte phenotypes, with a significant decrease in CD4+ single-positive T-cells. We also observed severe lymphopenia in Foxn1lacz mice caused by the premature decrease in T-cell production, resulting in a peripheral T-cell phenotype similar to de novo aged peripheral T-cells. Moreover, following T cell receptor stimulation, Foxn1lacz peripheral T cells had reduced IL-2 secretion and strong initial IFN-g responses, resembling aged wild-type peripheral T-cell responses. Lastly, influenza response in Foxn1lacz had a reduction in some aspects of T cell responses to influenza infection, similar to thymectomized mice. Our study shows an independent and direct impact of premature thymic involution on both thymopoiesis and peripheral immune niches likely contributing to immunosenescence and inflammaging as observed in the elderly population.
2025-03-21 | GSE264402 | GEO
Project description:Adipocyte deposition is believed to be a primary characteristic of age-related thymic involution, but the underlying cellular and molecular mechanisms remain unknown. We show here that thymic mesenchymal stromal cells (tMSCs) have a higher tendency to differentiate into adipocytes and melanocortin-2 receptor accessory protein (MRAP) is a potential driver of tMSCs adipogenesis. Furthermore, we discover that thymosin-α1 promotes MRAP expression in tMSCs through FoxO1 signaling pathway. Additionally, the proportion of tMSCs increase in older mice compared to young mice. Importantly, MRAP is also necessary for human thymic MSCs to differentiate into adipocytes when exposed to thymosin-α1. Single-cell RNA-seq analysis of human thymus revealed an accumulation of tMSCs and adipocytes during aging, indicating a strong potential for adipogenic differentiation in age-related thymic involution. Thus, we have revealed MRAP as a key factor in promoting thymic MSCs adipogenesis triggered by thymosin-α1 and FoxO1 pathway, which may serve as potential target to hinder adiposity in age-related thymic involution.
2024-11-27 | GSE183261 | GEO
Project description:The thymus is a primary lymphoid organ that undergoes progressive age-associated involution, leading to reduced T cell output and impaired adaptive immunity. In this study, we employed scRNA-Seq as well as other approaches to reveal that medullary thymic epithelial cells (mTECs) produce excessive proinflammatory cytokines in the absence of Zfp36l1 and Zfp36l2, two RNA-binding proteins of TTP family. Consequently, FOXN1, a master regulator of pro-lymphopoietic genes in thymic epithelial cells, was down-regulated in young mice, which leads to premature thymic involution in knockout mice. These findings reveal a protective role for TTP family proteins in regulating cytokine levels within the thymic microenvironment and preventing premature thymic involution.
2026-01-09 | GSE315892 | GEO
Project description:In this study, we have, for the first time, depicted a comprehensive mapping of the mouse thymic N-glycoproteome with high depth and precision, and performed a detailed analysis of site-specific N-glycopeptide alterations during thymic involution using a naturally ageing mouse model.
2025-01-20 | PXD058066 |