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Potent and uniform fetal hemoglobin induction via base editing [Cut & Run]

ABSTRACT: Potent and uniform fetal hemoglobin induction via base editing [Cut & Run]

PROVIDER: PRJNA951690 | ENA |

REPOSITORIES: ENA

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Dataset's files

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			Action	DRS
	SRR24049332_1.fastq.gz	Fastqsanger.gz
	SRR24049332_2.fastq.gz	Fastqsanger.gz
	SRR24049333_1.fastq.gz	Fastqsanger.gz
	SRR24049333_2.fastq.gz	Fastqsanger.gz
	SRR24049334_1.fastq.gz	Fastqsanger.gz

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Potent and uniform fetal hemoglobin induction via base editing

Project description:Potent and uniform fetal hemoglobin induction via base editing

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Potent and uniform fetal hemoglobin induction via base editing [Cut & Run]

Project description:Genetic manipulations to increase fetal hemoglobin (HbF, α2γ2) in postnatal red blood cells (RBCs) can alleviate β-thalassemia and sickle cell disease. We compared five strategies in CD34+ hematopoietic stem and progenitor cells, using either Cas9 nuclease, which creates uncontrolled indel mixtures, or adenine base editors (ABE), which generate more precise nucleotide changes. The most potent modification was ABE generation of γ-globin (HBG1/HBG2) −175 A>G, which creates a promoter binding motif for the transcriptional activator TAL1. In erythroid colonies with >87.5% on-target edits, those with −175 A>G expressed 81 ± 7% HbF, versus 17 ± 11% in unedited controls. In comparison, HbF levels were lower and more variable in erythroid cells modified with either of two Cas9 nuclease strategies with similar editing efficiencies, being 32 ± 19% when a BCL11A repressor binding motif in the γ-globin promoter was targeted and 52 ± 13% when the +58 BCL11A erythroid enhancer was targeted. Contrary to currently accepted models of γ-globin regulation, HbF levels varied significantly with different Cas9 indels that disrupted the γ-globin promoter BCL11A binding motif. The −175 A>G base edit also induced HbF more potently than did the Cas9 nuclease approaches in RBCs generated after transplantation of modified normal or SCD patient CD34+ cells into mice. Our data suggest a strategy for potent, uniform induction of HbF and provide insights into γ-globin gene regulation. More generally, we demonstrate that diverse indels generated by Cas9 nuclease can cause unexpected variations in biological outcomes that can be circumvented by base editing, with important implications for therapeutic gene editing efforts.

2023-04-28 | GSE228819 | GEO

Potent and uniform fetal hemoglobin induction via base editing.

Project description:Inducing fetal hemoglobin (HbF) in red blood cells can alleviate β-thalassemia and sickle cell disease. We compared five strategies in CD34+ hematopoietic stem and progenitor cells, using either Cas9 nuclease or adenine base editors. The most potent modification was adenine base editor generation of γ-globin -175A>G. Homozygous -175A>G edited erythroid colonies expressed 81 ± 7% HbF versus 17 ± 11% in unedited controls, whereas HbF levels were lower and more variable for two Cas9 strategies targeting a BCL11A binding motif in the γ-globin promoter or a BCL11A erythroid enhancer. The -175A>G base edit also induced HbF more potently than a Cas9 approach in red blood cells generated after transplantation of CD34+ hematopoietic stem and progenitor cells into mice. Our data suggest a strategy for potent, uniform induction of HbF and provide insights into γ-globin gene regulation. More generally, we demonstrate that diverse indels generated by Cas9 can cause unexpected phenotypic variation that can be circumvented by base editing.

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Potent and uniform fetal hemoglobin induction via base editing

Project description:This SuperSeries is composed of the SubSeries listed below.

2023-04-28 | GSE228822 | GEO

CUT&RUN of erythroblasts upon perturbation of gamma-hemoglobin repressors (part II)

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NFI factors repress fetal hemoglobin in adult erythorid cells [CUT&RUN]

Project description:NFI factors repress fetal hemoglobin in adult erythorid cells [CUT&RUN]

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Project description:Molecular Dissection of Polycomb Group Protein-mediated Fetal Hemoglobin Repression [CUT&RUN]

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HIC2 represses BCL11A transcription to regulate hemoglobin switching during development [CUT&RUN]

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