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Epigenetic reactivation of tumor suppressor genes with CRISPRa technologies as precision therapy for hepatocellular carcinoma

ABSTRACT: Epigenetic reactivation of tumor suppressor genes with CRISPRa technologies as precision therapy for hepatocellular carcinoma

PROVIDER: PRJNA872201 | ENA |

REPOSITORIES: ENA

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Epigenetic reactivation of tumor suppressor genes with CRISPRa technologies as precision therapy for hepatocellular carcinoma

Project description:Chromatin plasticity can be exploited therapeutically for the selective manipulation of the epigenetic state, to ultimately restore transcriptional aberrations driving tumorigenesis. Abnormal epigenetic silencing of tumor suppressors genes (TSGs) is one of the carcinogenesis features in hepatocellular carcinoma (HCC). We computationally identified a panel of 12 putative TSGs exhibiting an anti-correlation between transcript abundance and promoter DNA methylation, while harbouring no genetic alterations. Silencing of at least one of these TSGs was bioinformatically predicted for any given HCC sample case, and encompassing all the subtypes of HCC, making it possible the targeting of any patient in a personalized manner. To specifically reactivate one or more TSGs of this panel we produced CRISPR activators (CRISPRa) multiplexing systems tailored to representative HCC lines. Unlike epigenetic drugs, which lack locus-selectivity, CRISPRa systems enabled a potent and precise (“at will”) reactivation of up to 4 TSG simultaneously. We show that reactivation of HHIP, MT1M, PZP, and TTC36 TSGs in Hep3B cells led to a functional decrease in cell viability, cell proliferation, and cell migration. By combining different effector domains, we identified a toolbox of epigenetic effectors and gRNAs for the functional interrogation and targeting of putative TSGs silenced in liver cancer patients. We outlined a highly personalized precision oncology approach for the treatment of aggressive forms of HCC.

2023-04-10 | GSE211837 | GEO

Epigenetic reactivation of tumor suppressor genes with CRISPRa technologies as precision therapy for hepatocellular carcinoma.

Project description:BackgroundEpigenetic silencing of tumor suppressor genes (TSGs) is a key feature of oncogenesis in hepatocellular carcinoma (HCC). Liver-targeted delivery of CRISPR-activation (CRISPRa) systems makes it possible to exploit chromatin plasticity, by reprogramming transcriptional dysregulation.ResultsUsing The Cancer Genome Atlas HCC data, we identify 12 putative TSGs with negative associations between promoter DNA methylation and transcript abundance, with limited genetic alterations. All HCC samples harbor at least one silenced TSG, suggesting that combining a specific panel of genomic targets could maximize efficacy, and potentially improve outcomes as a personalized treatment strategy for HCC patients. Unlike epigenetic modifying drugs lacking locus selectivity, CRISPRa systems enable potent and precise reactivation of at least 4 TSGs tailored to representative HCC lines. Concerted reactivation of HHIP, MT1M, PZP, and TTC36 in Hep3B cells inhibits multiple facets of HCC pathogenesis, such as cell viability, proliferation, and migration.ConclusionsBy combining multiple effector domains, we demonstrate the utility of a CRISPRa toolbox of epigenetic effectors and gRNAs for patient-specific treatment of aggressive HCC.

| S-EPMC10149030 | biostudies-literature

STRT RNAseq of pluripotent stem cells reprogrammed with CRISPRa

Project description:Transcriptome comparison of CRISPRa induced human pluripotent stem cell lines, control iPSC line induced with Sendai viral vectors, H9 embryonic stem cell line and human foreskin fibroblasts.

2018-06-07 | E-MTAB-6185 | biostudies-arrayexpress

Dynamic properties of transcriptional condensates modulate CRISPRa-mediated gene activation

Project description:Purpose: To identify differential expressed genes upon CRISPRa activation. Methods: 293T cells were activated by different CRISPRa systems and then collected for RNA sequencing at 48 hpf (hours post CRISPRa activation).

2024-10-05 | GSE278565 | GEO

DNA methylome analysis of human pluripotent stem cells reprogrammed with CRISPRa

Project description:Comparison of DNA methylation in CRISPRa induced human pluripotent stem cell lines, control iPSC line induced with Sendai viral vectors, H9 embryonic stem cell line and human foreskin fibroblasts.

2018-06-07 | E-MTAB-6194 | biostudies-arrayexpress

Multiplexed activation of endogenous genes by CRISPRa elicits potent anti-tumor immunity

Project description:Immunotherapy has transformed cancer treatment. However, current immunotherapy modalities face many limitations. Here, we developed a new form of immunotherapy that elicits anti-tumor immunity through multiplexed activation of endogenous genes. We leveraged the CRISPR activation (CRISPRa) system to directly augment the in situ expression of endogenous genes, and thereby the presentation of tumor antigens, leading to dramatic anti-tumor immune responses. Deploying this as a cell-based vaccination strategy showed efficacy in both prophylactic and therapeutic settings. Intratumoral adeno-associated virus delivery of CRISPRa libraries elicited strong anti-tumor immunity across multiple cancer types. Precision targeting of mutated gene sets eradicated a large fraction of established tumors at both local and distant sites. This treatment modality led to alterations of the tumor microenvironment, marked by enhanced T cell infiltration and anti-tumor immune signatures. Multiplexed endogenous gene activation may serve as a versatile and highly scalable strategy to elicit potent immune responses against cancer.

2020-04-14 | GSE133983 | GEO

Promoter or enhancer activation by CRISPRa rescues haploinsufficiency caused obesity

Project description:Haploinsufficiency, having only one functional copy of a gene, leads to a wide-range of human diseases. Using obesity as a disease model, we tested whether haploinsufficiency can be rescued by CRISPR-mediated activation (CRISPRa) of the normal allele. Haploinsufficiency of either SIM1 or MC4R, results in severe obesity in humans and mice. In transgenic mice, CRISPRa targeting of the Sim1 promoter or its ~270kb distant hypothalamic enhancer, rescued the obesity phenotype in Sim1 heterozygous mice. Interestingly, despite using a ubiquitous promoter for CRISPRa, Sim1 was upregulated only in tissues where the promoter or enhancer are active, suggesting that cis-regulatory elements can determine CRISPRa tissue-specificity. To evaluate the potential therapeutic use of CRISPRa, we injected CRISPRa-rAAV into the hypothalamus, leading to reversal of the obesity phenotype in Sim1 and Mc4r heterozygous mice. Our results show that CRISPRa can be developed as a gene regulation therapy (GRT) to treat altered gene dosage diseases.

2018-12-17 | GSE112250 | GEO

Reactivation of Tumor Suppressor in Breast Cancer by Enhancer Switching through NamiRNA Network

Project description:Reactivation of Tumor Suppressor in Breast Cancer by Enhancer Switching through NamiRNA Network

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STRT RNAseq of human foreskin fibroblasts undergoing CRISPRa reprogramming

Project description:Comparison of human foreskin fibroblasts with different guide RNA compositions undergoing CRISPRa-mediated reprogramming. Cell samples have been collected at days 4, 8 and 12 of pluripotency induction. Each time point has three conditions with either (1) pluripotent reprogramming factor promoter targeting guides (OMKSL), (2) EEA-motif targeting guides (36bp), or reprorgamming factor promoter and EEA-motif targeting guides (OMKSL+36bp). Control samples have been collected from non-treated foreskin fibroblasts.

2018-06-07 | E-MTAB-6186 | biostudies-arrayexpress

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Project description:Comparison of technologies

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