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ABSTRACT: Harnessing eukaryotic retroelement proteins for transgene insertion into human safe-harbor loci

PROVIDER: PRJNA910950 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR22677634_1.fastq.gz	Fastqsanger.gz
	SRR22677634_2.fastq.gz	Fastqsanger.gz
	SRR22677635_1.fastq.gz	Fastqsanger.gz
	SRR22677635_2.fastq.gz	Fastqsanger.gz
	SRR26641419_1.fastq.gz	Fastqsanger.gz

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Project description:Modular safe-harbor transgene insertion (MosTI) for targeted single-copy transgene and array insertion in C. elegans

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Apoa1, a safe harbor locus for therapeutic genome editing in the liver

Project description:Clinical application of somatic genome editing requires therapeutics that are generalizable to a broad range of patients. Targeted insertion of promoterless transgenes can ensure that edits are permanent, broadly applicable, while minimizing risks of off-target integration. In the liver, the Albumin locus is currently the only well characterized site for promoterless transgene insertion. Using an unbiased ChIP-seq approach, we here identify Apolipoprotein a1 (Apoa1) as one of the most highly expressed and accessible loci in mouse and human liver. We target the Apoa1 locus with Adeno-Associated Viral (AAV) delivery of CRISPR/Cas9, and achieve rates of 6 to 16% with no evidence of toxicity. We further show that the endogenous Apoa1 promoter can drive robust and sustained expression of therapeutic proteins such as factor IX (FIX) or apolipoprotein E (APOE). Finally, we demonstrate that Apoa1-targeted fumarylacetoacetate hydrolase (FAH) can correct and rescue the severe metabolic liver disease hereditary tyrosinemia type I. In summary, we identify and validate Apoa1 as novel safe harbor site for genome editing therapeutics.

2021-06-01 | GSE152993 | GEO

Therapeutic globin expression in thalassemia patient induced pluripotent stem cells from genomic safe harbors

Project description:The advent of human induced pluripotent stem (iPS) cells enables for the first time the derivation of unlimited numbers of patient-specific stem cells and holds great promise for regenerative medicine. However, realizing the full potential of iPS cells requires robust, precise and safe strategies for their genetic modification. Safe human iPS cell engineering is especially needed for therapeutic applications, as stem cell-based therapies that rely on randomly integrated transgenes pose oncogenic risks. Here we describe a strategy to genetically modify iPS cells from patients with beta-thalassemia in a potentially clinically relevant manner. Our approach is based on the identification and selection of “safe harbor” sites for transgene expression in the human genome. We show that thalassemia patient iPS cell clones harboring a transgene can be isolated and screened according to chromosomal position. We next demonstrate that iPS cell clones that meet our “safe harbor” criteria resist silencing and allow for therapeutic levels of beta-globin expression upon erythroid differentiation without perturbation of neighboring gene expression. Combined bioinformatics and functional analyses thus provide a robust and dependable approach for achieving desirable levels of transgene expression from selected chromosomal loci. This approach may be broadly applicable to introducing therapeutic or suicide genes into patient specific iPS cells for use in cell therapy.

2010-10-26 | GSE24901 | GEO

Genome-wide analysis of gene expression in human iPSCs and NSCs engineered by safe-harbor TALEN-mediated gene targeting

Project description:Human iPSCs and NSCs were engineered by AAVS1 and/or C13 safe-harbor TALENs which mediated targeted integration of various reporter genes at single or dual safe-harbor loci. Multiple clones of targeted human iPSCs were used to compare with parental untargeted NCRM5 iPSCs. Polyclonal targeted human NSCs were used to compare with their parental untargeted NCRM1NSCs or H9NSCs. Total RNA obtained from targeted human iPSCs or NSCs compared to untargeted control iPSCs or NSCs.

2014-09-01 | E-GEOD-55975 | biostudies-arrayexpress

Genome-wide analysis of gene expression in human iPSCs and NSCs engineered by safe-harbor TALEN-mediated gene targeting

2014-09-01 | GSE55975 | GEO

Selection of the target site is an inherent question for any project aiming for directed transgene integration. Genomic safe harbour (GSH) loci have been proposed as safe sites in the human genome for transgene integration. Although several sites have been characterised for transgene integration in the literature, most of these do not meet criteria set out for a GSH and the limited set that do have not been characterised extensively. Here, we conducted a computational analysis using publicly available data to identify 25 unique putative GSH loci that reside in active chromosomal compartments. We validated stable transgene expression and minimal disruption of the native transcriptome in three GSH sites in vitro using human embryonic stem cells (hESCs) and their differentiated progeny. Furthermore, for easy targeted transgene expression, we have engineered constitutive landing pad expression constructs into the three validated GSH in hESCs.

Project description:putative genomic safe harbour loci for transgene expression in human cells

| PRJEB49564 | ENA

Therapeutic globin expression in thalassemia patient induced pluripotent stem cells from genomic safe harbors

Project description:The advent of human induced pluripotent stem (iPS) cells enables for the first time the derivation of unlimited numbers of patient-specific stem cells and holds great promise for regenerative medicine. However, realizing the full potential of iPS cells requires robust, precise and safe strategies for their genetic modification. Safe human iPS cell engineering is especially needed for therapeutic applications, as stem cell-based therapies that rely on randomly integrated transgenes pose oncogenic risks. Here we describe a strategy to genetically modify iPS cells from patients with beta-thalassemia in a potentially clinically relevant manner. Our approach is based on the identification and selection of âsafe harborâ sites for transgene expression in the human genome. We show that thalassemia patient iPS cell clones harboring a transgene can be isolated and screened according to chromosomal position. We next demonstrate that iPS cell clones that meet our âsafe harborâ criteria resist silencing and allow for therapeutic levels of beta-globin expression upon erythroid differentiation without perturbation of neighboring gene expression. Combined bioinformatics and functional analyses thus provide a robust and dependable approach for achieving desirable levels of transgene expression from selected chromosomal loci. This approach may be broadly applicable to introducing therapeutic or suicide genes into patient specific iPS cells for use in cell therapy. iPS cell clones were derived from beta-thalassemia patients. A single copy of beta-globin transgene cis-linked to locus control region (LCR) elements and an excisable Neo-eGFP transcription unit were inserted into these cell clones. beta-globin expression was induced by erythroid differentiation.

2010-10-26 | E-GEOD-24901 | biostudies-arrayexpress

Transcriptomes of novel human genomic safe harbor sites for gene and cell therapies

Project description:Bulk RNA-sequencing experiments were performed to analyze the transcriptomic effects of such integrations into two newly established genomic safe harbor sites. Jurkat and HEK293T cells were edited to integrate CMV-mRuby expressing cassette into Rogi2 genomic safe harbor site using Cas9 RNP

2022-02-11 | E-MTAB-11289 | biostudies-arrayexpress

Project description:Schistosoma mansoni genome safe harbor editing

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HP1b Q4114.D.mel 3rd Instar Larvae Nuclei HP1c Mutant

Project description:modENCODE_submission_4184 This submission comes from a modENCODE project of Gary Karpen. For full list of modENCODE projects, see http://www.genome.gov/26524648 Project Goal: We aim to determine the locations of 125 chromosomal proteins across the Drosophila melanogaster genome. The proteins under study are involved in basic chromosomal functions such as DNA replication, gene expression, gene silencing, and inheritance. We will perform Chromatin ImmunoPrecipitation (ChIP) using genomic tiling arrays. We will initially assay localizations using chromatin from three cell lines and two embryonic stages, and will then extend the analysis of a subset of proteins to four additional animal tissues/stages For data usage terms and conditions, please refer to http://www.genome.gov/27528022 and http://www.genome.gov/Pages/Research/ENCODE/ENCODEDataReleasePolicyFinal2008.pdf EXPERIMENT TYPE: CHIP-chip. BIOLOGICAL SOURCE: Strain: HP1c mutant(official name : HP1c[f04929] genotype : w[1118]; PBac{w[+mC]=WH}HP1c[f04929] outcross : unknown transgene : PBac insertion tags : Transposon description : Insertion of PBac transgene disrupts Hp1c gene (Gene disruption project). Developmental Stage: 3rd Instar Larvae; Genotype: w[1118]; PBac{w[+mC]=WH}HP1c[f04929]; Transgene: PBac insertion; NUMBER OF REPLICATES: 4; EXPERIMENTAL FACTORS: Strain HP1c mutant(official name : HP1c[f04929] genotype : w[1118]; PBac{w[+mC]=WH}HP1c[f04929] outcross : unknown transgene : PBac insertion tags : Transposon description : Insertion of PBac transgene disrupts Hp1c gene (Gene disruption project). Antibody HP1b Q4114 (target is HP1b); Developmental Stage 3rd Instar Larvae

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