The role of RPA1 in T cell
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE189548 | GEO | 2024/06/15
REPOSITORIES: GEO
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Project description:As a single strand DNA binding protein, RPA1 participates in various cellular processes including DNA replication and DNA repair. However, the role of RPA1 in T cells is largely unknown. We generated a mouse model in which RPA1 was specifically deleted in T cells. Through single cell RNA sequencing, we reveal the immune landscape in RPA1 conditional knockout mice.
2024-06-15 | GSE189929 | GEO
Project description:As a single strand DNA binding protein, RPA1 participates in various cellular processes including DNA replication and DNA repair. However, the role of RPA1 in T cells is largely unknown. We generated a mouse model in which RPA1 was specifically deleted in T cells. Through single cell RNA sequencing, we reveal the immune landscape in RPA1 conditional knockout mice.
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Project description:Replication protein A(RPA), a ssDNA binding protein complex, participates in DNA replication, recombination and damage repair, but its physiological function remains elusive. Here, we show that heterozygous Rpa1 knockout mice were developmentally normal, but hypersensitive to ageing and high-fat-diet (HFD) induced hepatic steatosis. Liver specific deletion of Rpa1 leads to impaired lipid beta-oxidation, hepatic steatosis and subsequently hepatocellular carcinoma (HCC). Assays for RNA-seq, pull-down and transposase-accessible chromatin sequencing (ATAC-seq) reveal that RPA1 is required for transcription of a subgroup of lipid metabolic genes via altering chromatin accessibility landscape. Thus, our results suggest that RPA1 is a critical regulator of gene transcription and chromatin remodeling, linking a guardian of genome stability to lipid metabolic homeostasis.
2024-12-21 | GSE123890 | GEO
Project description:Replication protein A1 (RPA1) is a single-stranded DNA binding protein that is known to participate in DNA replication, recombination and damage repair. However, little is known about RPA1’s role in controlling chromatin architecture and gene transcription. Further, physiological functions of RPA1 in mouse tissues still remain exclusive. Here we show that Rpa1 heterozygous mice developed age-depended fatty liver disease and are more susceptible to hepatic steatosis in response to high-fat diet. Liver specific deletion of Rpa1 impairs fatty acid oxidation, leading to hepatic steatosis and high incidence of hepatocellular carcinoma. Transcriptome analysis identified down-regulation of fatty acid oxidation related genes. Cleavage Under Targets and Tagmentation (CUT&Tag) and Assay for transposase-accessible chromatin using sequencing (ATAC-seq) revealed that RPA1 binds and regulates chromatin accessibility in regulatory regions of a group of genes involved in lipid metabolism in liver. Further, down-regulation of RPA1 was found in patients with fatty liver disease. Thus, our results not only established that RPA1 is critical controller of chromatin architecture and regulator of gene transcription, but also provided new insights into the epigenetic mechanism of fatty liver disease, which could inform future therapy.
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Project description:The peripheral T cell pool is maintained at dynamic homeostasis throughout life. This is achieved through fine-tuning of thymic output and self-renewal of naïve T cells. Dysregulation of T cell homeostasis has been implicated in autoimmune diseases, yet little is known about the homeostatic mechanisms. Here, we report that the replication protein A1 (RPA1) is upregulated during T cell activation. Utilizing T cell-specific Rpa1-deficient (Rpa1fl/fl Cd4-cre) mice, we find that loss of Rpa1 restrains peripheral CD8+ T cell population and limits TCR repertoire diversity. Clinical analysis reveals that the mRNA level of RPA1 is reduced in patients with ulcerative colitis. Accordingly, Rpa1fl/fl Cd4-cre mice exhibit increased susceptibility to inflammatory diseases, including colitis and hepatitis. Mechanistically, RPA1 deficiency triggers necroptotic T cell death following TCR engagement, which in turn results in damage-associated molecular patterns (DAMPs) leakage and leukocyte recruitment, consequently exacerbating inflammatory damage. These studies thus uncover that RPA1 acts as a guardian of T cell clonal expansion that is essential for T cell homeostasis.
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Project description:Lysine crotonylation (Kcr) is a recently-identified protein short-chain acylation. We have previously reported that chromodomain Y-like transcription corepressor CDYL acts as a crotonyl-CoA hydratase and negatively regulates histone Kcr. However, the global crotonylome of CDYL-regulated Kcr on non-histone substrates remains unclear. Using proteome-wide quantitative Kcr analysis, we identified 14,311 Kcr sites across 3,734 proteins in HeLa cells, providing by far the largest crotonylome data set from a single study. Upon depletion of CDYL, 1,141 Kcr sites from 759 proteins were increased by more than 1.5 fold, and 933 Kcr sites from 528 proteins were decreased by more than 0.67 fold. Upregulated crotonylome alterations upon CDYL depletion include components from diverse cellular pathways such as RNA splicing, DNA replication, and amino acid metabolism. Specifically, CDYL regulates K88 and K379 of crotonylation on RPA1, which affects its binding to other DNA repair factors including BLM, DNA2L, RAD50 and WRN. We showed evidence that CDYL-mediated RPA1 crotonylation is critical for the homologous recombination (HR) repair of camptothecin (CPT)-induced DNA damage. Together, our results provide a broad lysine crotonylome in response to CDYL and shed new light on the role of RPA1 Kcr in DNA repair, implicating functional importance of Kcr on non-histone substrates in diverse cellular processes.
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Project description:Transcription factor access to regulatory elements is prevented by the nucleosome. Heat shock factor 1 (HSF1) is a winged helix transcription factor that plays roles in control and stressed conditions by gaining access to target elements, but mechanisms of HSF1 access have not been well known in mammalian cells. We show a physical interaction between the wing motif of human HSF1 and replication protein A (RPA), which is involved in DNA metabolism. Depletion of RPA1 abolishes HSF1 access to the promoter of HSP70 in unstressed conditions, and delays its rapid activation in response to heat shock. The HSF1-RPA complex leads preloading of RNA polymerase II and opens chromatin structure by recruiting a histone chaperone FACT. Furthermore, this interaction is required for melanoma cell proliferation. These results provide a mechanistic basis for constitutive HSF1 access to nucleosomal DNA, which is important for both basal and inducible gene expression. To examine whether the HSF1-RPA complex regulates the expression of genes, mRNA levels in MEFs with/without HSF1- or RPA1-shRNA were analyzed by DNA microarray analysis using GeneChip Mouse Gene 1.0 ST Arrays (Affymetrix).
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Project description:To examine the molecular mechanisms by which RPA1 regulates transcription in liver, we conducted immunoprecipitation followed by mass spectrometry to characterize RPA1-associated proteins in mouse liver.
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