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Exonic knock-out/in gene editing in hematopoietic stem and progenitor cells fully rescues RAG1 immunodeficiency [RNA-Seq]

ABSTRACT: Recombination Activating Genes (RAG) are tightly regulated during lymphoid differentiation and their mutations cause a spectrum of severe immunological disorders. Haematopoietic stem/progenitor cell (HSPC) transplantation is the treatment of choice but limited by donor availability and toxicity. To overcome these issues, we developed and validated gene editing (GE) strategies targeting a corrective sequence into the human RAG1 gene by homology-directed repair (HDR). Off-target and RNA-Seq analyses were performed on edited human and patient-derived HSPCs to assesse the genome integrity and the trascriptomic profile. Whereas integration into intron 1 achieved suboptimal levels of correction, in-frame insertion into exon 2 drove faithful recapitulation of physiologic hRAG1 expression and activity.

ORGANISM(S): Homo sapiens

PROVIDER: GSE244672 | GEO | 2023/12/31

REPOSITORIES: GEO

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Exonic knock-out/in gene editing in hematopoietic stem and progenitor cells fully rescues RAG1 immunodeficiency [GUIDE2]

Project description:Recombination Activating Genes (RAG) are tightly regulated during lymphoid differentiation and their mutations cause a spectrum of severe immunological disorders. Haematopoietic stem/progenitor cell (HSPC) transplantation is the treatment of choice but limited by donor availability and toxicity. To overcome these issues, we developed and validated gene editing (GE) strategies targeting a corrective sequence into the human RAG1 gene by homology-directed repair (HDR). Off-target and RNA-Seq analyses were performed on edited human and patient-derived HSPCs to assesse the genome integrity and the trascriptomic profile. Whereas integration into intron 1 achieved suboptimal levels of correction, in-frame insertion into exon 2 drove faithful recapitulation of physiologic hRAG1 expression and activity.

2023-12-31 | GSE244671 | GEO

Exonic knock-out/in gene editing in hematopoietic stem and progenitor cells fully rescues RAG1 immunodeficiency [GUIDE1]

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Exonic knock-out/in gene editing in hematopoietic stem and progenitor cells fully rescues RAG1 immunodeficiency [OFFTARGET]

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Exonic knock-out/in gene editing in hematopoietic stem and progenitor cells fully rescues RAG1 immunodeficiency

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The In Vivo Pattern of Binding of RAG1 and RAG2 to Antigen Receptor Loci

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2010-04-20 | GSE21207 | GEO

The In Vivo Pattern of Binding of RAG1 and RAG2 to Antigen Receptor Loci

Project description:The critical initial step in V(D)J recombination, binding of RAG1 and RAG2 to recombination signal sequences flanking antigen receptor V, D, and J gene segments, has not previously been characterized in vivo. Here we demonstrate that RAG protein binding occurs in a highly focal manner to a small region of active chromatin encompassing IgÎº and TcrÎ± J gene segments and Igh and TcrÎ² J and J-proximal D gene segments. Formation of these small RAG-bound regions, which we refer to as recombination centers, occurs in a developmental stage- and lineage-specific manner. Each RAG protein is independently capable of specific binding within recombination centers. While RAG1 binding is restricted to regions containing recombination signal sequences, RAG2 binds extremely broadly in a pattern that mirrors that of trimethylated lysine 4 of histone 3. We propose that recombination centers coordinate V(D)J recombination by providing discrete sites within which gene segments are captured for recombination. RAG2 binding was analyzed in wild type, RAG2-/-Î², and D708A-RAG1-/-Î² thymocytes. Histone modification H3K4me3 was analyzed in D708A-RAG1-/-Î² and wild type thymocytes.

2010-04-19 | E-GEOD-21207 | biostudies-arrayexpress

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2024-04-28 | GSE192597 | GEO

The role of nitric oxide synthase activity in connection with induced resistance against low-dose hyper-radiosensitivity

Project description:The cells harvested for microarray analysis were high-dose rate (HDR) irradiated, low-dose rate (LDR) irradiated or unirradiated T-47D cells. The HDR-irradiated cells were harvested 24h after a dose of 0.3 Gy at 35 Gy/h, a time where hyper-radiosensitivity (HRS) had returned. The HRS-deficient LDR-irradiated cells were harvested 2 months after a dose of 0.3 Gy at 0.3 Gy/h. LDR-irradiated vs. Control (unirradiated) contains 4 biological replicates. HDR- vs. LDR-irradiated contains 3 biological replicates. HDR-irradiated vs. Control contains 4 biological replicates.

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