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IPSCs-derived NK cells with site-specific integration of CAR19 and IL24 at the multi-copy rDNA locus enhanced antitumor activity and proliferation

ABSTRACT: iPSCs-derived NK cells with site-specific integration of CAR19 and IL24 at the multi-copy rDNA locus enhanced antitumor activity and proliferation

PROVIDER: PRJNA1082250 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR28164300_1.fastq.gz	Fastqsanger.gz
	SRR28164300_2.fastq.gz	Fastqsanger.gz
	SRR28164289_1.fastq.gz	Fastqsanger.gz
	SRR28164289_2.fastq.gz	Fastqsanger.gz
	SRR28164290_1.fastq.gz	Fastqsanger.gz

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iPSCs-derived NK cells with site-specific integration of CAR19 and IL24 at the multi-copy rDNA locus enhanced antitumor activity and proliferation

Project description:The generation of CAR-NK cells using induced pluripotent stem cells (iPSCs) has emerged as one of the paradigms for manufacturing off-the-shelf universal immunotherapy.iPSCs here were site-specifically integrated at the ribosomal DNA (rDNA) locus with interleukin 24 (IL24) and CD19-specific chimeric antigen receptor (CAR19), and successfully differentiated into iPSCs-derived NK (iNK) cells followed by expansion using magnetic beads in vitro. To explore the anti-tumor phenotype of CAR-loaded iNK cells and the likely role of IL24, RNA from four iNK cells was isolated, sequenced, and gene expression of the cell populations were compared.

2024-04-05 | GSE260573 | GEO

Quelling targets the rDNA locus and functions in rDNA copy number control.

Project description:BackgroundRNA silencing occurs in a broad range of organisms. Although its ancestral function is probably related to the genome defense mechanism against repetitive selfish elements, it has been found that RNA silencing regulates different cellular processes such as gene expression and chromosomal segregation. In Neurospora crassa, a RNA silencing mechanism, called quelling, acts to repress the expression of transgenes and transposons, but until now no other cellular functions have been shown to be regulated by this mechanism.ResultsHere, we detected by northern blotting endogenous short interfering RNA (siRNAs) from the repetitive ribosomal DNA locus (rDNA) that are loaded onto the argonaute protein QDE-2. Moreover, we found a bidirectional transcription that can generate double strand RNA (dsRNA) molecules. Interestingly, quelling mutants have a reduced rDNA gene copy number.ConclusionOur finding could suggest a new biological function for RNA silencing in the maintenance of the integrity and stability of the Neurospora rDNA locus.

| S-EPMC2650698 | biostudies-literature

Paired CRISPR/Cas9 Nickases Mediate Efficient Site-Specific Integration of F9 into rDNA Locus of Mouse ESCs.

Project description:Hemophilia B (HB) is an X-linked recessive bleeding disorder, caused by F9 gene deficiency. Gene therapy combined with the CRISPR/Cas9 technology offers a potential cure for hemophilia B. Now the Cas9 nickase (Cas9n) shows a great advantage in reducing off-target effect compared with wild-type Cas9. In this study, we found that in the multicopy ribosomal DNA (rDNA) locus, the homology directed recombination (HDR) efficiency induced by sgRNA-Cas9n was much higher than sgRNA-Cas9, meanwhile without off-target in six predicted sites. After co-transfection into mESCs with sgRNA-Cas9n and a non-viral rDNA targeting vector pMrnF9, harboring the homology donor template and the human F9 expression cassette, a recombination efficiency of 66.7% was achieved and all targeted clones were confirmed to be site-specific integration of F9 in the rDNA locus by PCR and southern blotting. Targeted mESCs retained the main pluripotent properties and were then differentiated into hepatic progenitor like cells (HPLCs) and mature hepatocytes, which were characterized by hepatic markers and functional assays. Importantly, the differentiated cells could transcribe exogenous F9 and secrete coagulation factor IX (FIX) proteins, suggesting active transcription and stable inheritance of transgenes in the rDNA locus. After intrasplenical transplantation in severe combined immune deficiency (SCID) mice, targeted HPLCs could survive and migrate from spleen to liver, resulting in secretion of exogenous FIX into blood. In summary, we demonstrate an efficient and site-specific gene targeting strategy in rDNA locus for stem cell-based gene therapy for hemophilia B.

| S-EPMC6213315 | biostudies-literature

ZEB2 locus regulation in differentiating iPSCs

Project description:ZEB2 locus regulation in differentiating iPSCs

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BPTF Depletion Enhances NK Cell Mediated Antitumor Immunity

Project description:In mouse models, the bromodomain PHD finger transcription factor (BPTF) chromatin remodeling subunit in tumor cells suppresses natural killer (NK) cell antitumor activity. In vitro, BPTF suppresses NK cell cytolytic activity to mouse and human cancer cell lines, demonstrating a conserved function.

2017-04-28 | GSE85756 | GEO

Modeling Fanconi Anemia pathogenesis and therapeutics using integration-free patient iPSCs [ChIP-seq]

Project description:We compared the epigenetic status of the mutant and disease-free iPSCs at the whole genome level. Whole epigenome profiling based on trimethylated H3K4 (H3K4me3) showed concordant epigenetic remodeling in the two corrected clones when compared with two mutant iPSC clones. Examination of the trimethylated H3K4 histone modification in Fanconi anemia patient iPSCs before and after gene correction

2014-05-21 | E-GEOD-57827 | biostudies-arrayexpress

Modeling Fanconi Anemia pathogenesis and therapeutics using integration-free patient iPSCs [RNA-seq]

Project description:We compared the epigenetic status of the mutant and disease-free iPSCs at the whole genome level. Whole epigenome profiling based on trimethylated H3K4 (H3K4me3) showed concordant epigenetic remodeling in the two corrected clones when compared with two mutant iPSC clones. Examination of genome-wide gene expression in Fanconi anemia patient iPSCs before and after gene correction

2014-05-21 | E-GEOD-57826 | biostudies-arrayexpress

Enhanced tumor growth inhibition by mesenchymal stem cells derived from iPSCs with targeted integration of interleukin24 into rDNA loci.

Project description:Induced pluripotent stem cells (iPSCs) are a promising source of mesenchymal stem cells (MSCs) for clinical applications. In this study, we transformed human iPSCs using a non-viral vector carrying the IL24 transgene pHrn-IL24. PCR and southern blotting confirmed IL24 integration into the rDNA loci in four of 68 iPSC clones. We then differentiated a high expressing IL24-iPSC clone into MSCs (IL24-iMSCs) that showed higher expression of IL24 in culture supernatants and in cell lysates than control iMSCs. IL24-iMSCs efficiently differentiated into osteoblasts, chondrocytes and adipocytes. Functionally, IL24-iMSCs induced in vitro apoptosis in B16-F10 melanoma cells more efficiently than control iMSCs when co-cultured in Transwell assays. In vivo tumor xenograft studies in mice demonstrated that IL24-iMSCs inhibited melanoma growth more than control iMSCs did. Immunofluorescence and histochemical analysis showed larger necrotic areas and cell nuclear aggregation in tumors with IL24-iMSCs than control iMSCs, indicating that IL24-iMSCs inhibited tumor growth by inducing apoptosis. These findings demonstrate efficient transformation of iPSCs through gene targeting with non-viral vectors into a rDNA locus. The ability of these genetically modified MSCs to inhibit in vivo melanoma growth is suggestive of the clinical potential of autologous cell therapy in cancer.

| S-EPMC5522332 | biostudies-literature

Ribosomal DNA Copy Number Variation is Coupled with DNA Methylation Changes at the 45S rDNA Locus.

Project description:The human ribosomal DNA (rDNA) copy number (CN) has been challenging to analyse, and its sequence has been excluded from reference genomes due to its highly repetitive nature. The 45S rDNA locus encodes essential components of the cell, nevertheless rDNA displays high inter-individual CN variation that could influence human health and disease. CN alterations in rDNA have been hypothesized as a possible factor in autism spectrum disorders (ASD) and were shown to be altered in Schizophrenia patients. We tested whether whole-genome bisulphite sequencing can be used to simultaneously quantify rDNA CN and measure DNA methylation at the 45S rDNA locus. Using this approach, we observed high inter-individual variation in rDNA CN, and limited intra-individual copy differences in several post-mortem tissues. Furthermore, we did not observe any significant alterations in rDNA CN or DNA methylation in Autism Spectrum Disorder (ASD) brains in 16 ASD vs 11 control samples. Similarly, no difference was detected when comparing neurons form 28 Schizophrenia (Scz) patients vs 25 controls or oligodendrocytes from 22 Scz samples vs 20 controls. However, our analysis revealed a strong positive correlation between CN and DNA methylation at the 45S rDNA locus in multiple tissues. This was observed in brain and confirmed in small intestine, adipose tissue, and gastric tissue. This should shed light on a possible dosage compensation mechanism that silences additional rDNA copies to ensure homoeostatic regulation of ribosome biogenesis.

| S-EPMC10305490 | biostudies-literature

HBV-KMT2B integrated human induced pluripotent stem cells (KMT2B-Int iPSCs) vs heterozygous mutated KMT2B iPSCs (KMT2B-HT iPSCs) vs homozygous mutated KMT2B iPSCs (KMT2B-KO iPSCs) vs their original iPSCs (KMT2B-WT iPSCs)

Project description:HBV-KMT2B integrated human induced pluripotent stem cells (KMT2B-Int iPSCs) vs heterozygous mutated KMT2B iPSCs (KMT2B-HT iPSCs) vs homozygous mutated KMT2B iPSCs (KMT2B-KO iPSCs) vs their original iPSCs (KMT2B-WT iPSCs)

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