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CXXC finger protein 1 is critical for T cell intrathymic development through regulating H3K4 trimethylation [ChIP-Seq]

ABSTRACT: T cell development in the thymus is largely controlled by an epigenetic program involving in both DNA methylation and histone modifications. Previous studies have identified Cxxc1 as a regulator of both cytosine methylation and histone 3 lysine 4 trimethylation (H3K4me3). However, it is unknown whether Cxxc1 plays a role in thymocyte development. Here we show that T cell development in the thymus is severely impaired in Cxxc1-deficient mice. Furthermore, we identify genome-wide Cxxc1 binding sites and H3K4me3 modification sites in wild-type and Cxxc1-deficient thymocytes. Our results demonstrate that Cxxc1 directly controls the expression of key genes important for thymocyte survival such as RORγt and for TCR signaling including Zap70 and CD8, through maintaining the appropriate H3K4me3 on their promoters. Importantly, we show that RORγt, a direct target of Cxxc1, can rescue the survival defects in Cxxc1-deficient thymocytes. Our data strongly support a critical role of Cxxc1 in thymocyte development.

ORGANISM(S): Mus musculus

PROVIDER: GSE79974 | GEO | 2016/04/14

SECONDARY ACCESSION(S): PRJNA317546

REPOSITORIES: GEO

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CXXC finger protein 1 is critical for T cell intrathymic development through regulating H3K4 trimethylation [RNA-Seq]

Project description:T cell development in the thymus is largely controlled by an epigenetic program involving in both DNA methylation and histone modifications. Previous studies have identified Cxxc1 as a regulator of both cytosine methylation and histone 3 lysine 4 trimethylation (H3K4me3). However, it is unknown whether Cxxc1 plays a role in thymocyte development. Here we show that T cell development in the thymus is severely impaired in Cxxc1-deficient mice. Furthermore, we identify genome-wide Cxxc1 binding sites and H3K4me3 modification sites in wild-type and Cxxc1-deficient thymocytes. Our results demonstrate that Cxxc1 directly controls the expression of key genes important for thymocyte survival such as RORγt and for TCR signaling including Zap70 and CD8, through maintaining the appropriate H3K4me3 on their promoters. Importantly, we show that RORγt, a direct target of Cxxc1, can rescue the survival defects in Cxxc1-deficient thymocytes. Our data strongly support a critical role of Cxxc1 in thymocyte development.

2016-04-14 | GSE79975 | GEO

Role of CxxC-finger Protein 1 in the Establishment of Epigenetic Landscapes in Mouse Oocytes

Project description:During oogenesis, oocytes gain competence to accomplish meiotic maturation and prepare for embryonic development following fertilization. Trimethylated histone H3 on lysine-4 (H3K4me3) mediates a wide range of nuclear events during these processes. Oocyte-specific knockout of CxxC-finger protein 1 (CXXC1, also known as CFP1), the chromatin-binding subunit of SETD1 methyltransferase, impairs the H3K4me3 accumulation during murine oogenesis and caused changes in chromatin configurations. This study investigated the changes of genomic H3K4me3 landscapes in oocytes after Cxxc1 knockout, as well as the influences of H3K4me3 changes on other epigenetic marks including DNA methylation, H3K27me3, H2AK119ub1, and H3K36me3. Chromatin immunoprecipitation and sequencing results indicated that H3K4me3 is globally decreased after abolishing Cxxc1, including both the promoter region and the gene body. The results also demonstrate that CXXC1 and another histone H3 methyltransferase MLL2 have nonoverlapping roles in mediating H3K4 trimethylation during oogenesis. In addition, Cxxc1 deletion caused a significant decrease of DNA methylation level in oocytes, and affected H3K27me3 and H2AK119ub1 distributions in the maternal genome, particularly at the regions that have high DNA methylation levels. The changes of epigenetic networks caused by Cxxc1 deletion correlated with transcription changes of the genes in the corresponding genomic regions. Taken together, this study provided mechanistic explanations underlying the phenotypes and molecular defects in Cxxc1 deleted oocytes, and highlighted a role of CXXC1 in orchestrating multiple factors to build up the appropriate epigenetic states of maternal genome during oocyte maturation.

2021-02-04 | GSE159581 | GEO

Epigenetic initiation of the Th17 differentiation programme is promoted by Cxxc finger protein 1

Project description:IL-6/STAT3 signalling is known to initiate the Th17 differentiation programme, but the upstream regulatory mechanisms remain minimally explored. Here, we show that Cxxc finger protein 1 (Cxxc1) promoted the generation and stability of Th17 cells as an epigenetic regulator and prevented their differentiation into Treg cells. Mice with a T cell-specific deletion of Cxxc1 were protected from experimental autoimmune encephalomyelitis and were more susceptible to Citrobacter rodentium infection. Cxxc1-deficient T cells acquired a Treg cell-biased programme that dominantly suppressed Th17 cell generation via IL-6Rα production. Cxxc1 deficiency decreased IL-6Rα expression and impeded IL-6/STAT3 signalling, whereas the overexpression of IL-6Rα could reverse the defects seen in Cxxc1-deficient Th17 cells in vitro and in vivo. Genome-wide occupancy analysis revealed that Cxxc1 bound to Il6rα gene loci in the Th17 programme by maintaining the appropriate H3K4me3 modification of its promoter. Therefore, these data highlight that Cxxc1 as a key regulator governs the balance between Th17 and Treg cells by controlling the expression of IL-6Rα, which subsequently affects IL-6/STAT3 signalling and has a direct impact on Th17-related autoimmune diseases.

2020-04-10 | GSE132208 | GEO

Differential expression of circRNAs discriminates between different maturational stages of human intrathymic thymocytes.

Project description:Circular RNAs (circRNAs) are stable single stranded RNA molecules which form a covalently closed continuous loop. They are involved in multiple biological processes, functioning mainly through interactions with microRNAs and proteins or by the expression of specific peptides. Preliminary data exist on circRNA expression in different peripheral blood cell populations. Deregulation of circRNAs has been shown to be key in the development of T-cell acute lymphoblastic leukemia (T-ALL). However, a detailed analysis on circRNAs expression in intrathymic thymocyte populations was still missing and might be key to understanding thymus development as well as tumours arising in the lymphoblastic line. The aim of this study was to investigate whether circRNAs are differentially expressed in thymocytes at different maturational stages during the intrathymic differentiation process.

2022-04-27 | GSE178889 | GEO

CxxC Finger Protein 1-mediated Histone H3 Lysine-4 Trimethylation is Essential for Proper Meiotic Crossover Formation in Mice

Project description:CXXC finger protein 1 (Cfp1) is a DNA-binding component of the SETD1 methyltransferase complex, targets SETD1A/B to most CpG islands (CpGI), and mediates the generation of H3K4me3. Deficiency of CFP1 in mice leads to pre-implantation lethality. Previous data suggest an indispensable role of CFP1 in germ cell development and meiosis. However, it remains unclear if CFP1-mediated H3K4 trimethylation is also required for the earliest stages of meiosis in both male and female germ cells. Here, we revealed that Cxxc1 deletion caused a decrease of H3K4me3 levels in spermatocytes after the zygotene stage, impaired double strand breaks (DSBs) repairing, and crossover formation in meiotic prophase. As the results, Cxxc1-deleted spermatocytes failed to complete meiosis and were arrested at the meiosis II. ChIP-seq results revealed that H3K4me3 globally descreased at transcriptional start sites in Cxxc1-null spermatocytes at the leptotene/zygotene and pathytene stages.RNA-seq at different stages revealed an earlier expression of genes within the spermatogenesis pathway in Cxxc1-null spermatocytes. These results indicated that CFP1 is required for H3K4me3 accumulation at the gene promoters of male germ cells and play a key role in regulating programed gene expression that is essential for spermatogenesis.

2020-03-11 | GSE133636 | GEO

The thymocyte-specific RNA-binding protein Arpp21 provides TCR repertoire diversity by binding to the 3'-UTR and promoting Rag1 mRNA expression

Project description:The regulation of thymocyte development by RNA-binding proteins (RBPs) is largely unexplored. We identified 642 RBPs in the thymus and focused on Arpp21, which shows selective and dynamic expression in early thymocytes. Arpp21 was downregulated in response to T cell receptor (TCR) and Ca2+ signals. Downregulation required Stim1/Stim2 and CaMK4 expression and involved Arpp21 protein phosphorylation, polyubiquitination and proteasomal degradation. Arpp21 directly bound RNA through its R3H domain, with a preference for uridine-rich motifs, promoting the expression of target mRNAs. Analysis of the Arpp21-bound transcriptome revealed strong interactions with the Rag1 3'-UTR. Arpp21-deficient thymocytes showed reduced Rag1 expression, delayed TCR rearrangement and a less diverse TCR repertoire. This phenotype was recapitulated in Rag1 3'-UTR mutant mice harboring a deletion of the Arpp21 response region. These findings show how thymocyte-specific Arpp21 promotes Rag1 expression to enable TCR repertoire diversity until signals from the TCR terminate Arpp21 and Rag1 activities.

2023-03-31 | MSV000091606 | MassIVE

Intrathymic T-cell selection

Project description:Comparisons between untreated primary cells T-cell precursors from the thymus. CD69- thymocytes are from Zap70-deficent mice and are >95% CD4+CD8+. These cells fail to generate intrathymic TCR signals as a result of their lacking Zap70 molecules, and are thus representative of "preselection" CD4+CD8+ thymocytes. The CD69hi population comes from wildtype mice and is heterogeneous for CD4 and CD8 expression. These cells have been intrathymically TCR-signaled and are undergoing selection.

2010-06-10 | E-GEOD-2262 | biostudies-arrayexpress

Intrathymic T-cell selection

2005-03-07 | GSE2262 | GEO

Analysis of Differentially Expressed Genes in sorted CD4+ CD8+ doubl positive (DP) thymocytes from wild type (WT) and NSRP1CD4Cre (KO) mice

Project description:NSrp70 deficiency (NSRP1f/fCD4Cre) profoundly perturbed the late development of DP thymocytes, leading to a significant reduction of single positive (SP) cells in the thymus and peripheral lymphoid tissues. To gain further insight how NSrp70 controls thymocyte development from DP stage, we performed RNA-seq analysis after sorting DP thymocytes from WT and Nsrp1 cKO mice.

2021-06-15 | GSE168379 | GEO

Analysis of Differentially Expressed Genes in sorted CD69+ double positive (DP) thymocytes from wild type (WT) and NSRP1CD4Cre (KO) mice

Project description:NSrp70 deficiency (NSRP1f/fCD4Cre) profoundly perturbed the late development of DP thymocytes, leading to a significant reduction of single positive (SP) cells in the thymus and peripheral lymphoid tissues. To gain further insight into how NSrp70 controls thymocyte development from CD69+ DP stage, we performed RNA-seq analysis after sorting CD69+ DP thymocytes from WT and Nsrp1 cKO mice.

2020-06-27 | GSE153389 | GEO

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