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Yao, Qiuming

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Yao

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Qiuming

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Yao, Qiuming
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    Augmenting and Directing Robust, Long-Range CRISPR-Mediated Activation in Human Cells
    (Springer Science and Business Media LLC, 2021-08-05) Tak, Y. Esther; Horng, Joy E.; Perry, Nicholas T.; Schultz, Hayley; Iyer, Sowmya; Yao, Qiuming; Zou, Luli S.; Aryee, Martin; Pinello, Luca; Joung, Keith
    Epigenetic editing is an emerging technology that uses artificial transcription factors (aTFs) to regulate expression of a target gene. Although human genes can be robustly upregulated by targeting aTFs to promoters, the activation induced by targeting aTFs to distal transcriptional enhancers is substantially less robust and consistent. Here we show that long-range activation using CRISPR-based aTFs in human cells can be made more efficient and reliable by concurrently targeting an aTF to the target gene promoter. We used this strategy to direct target gene choice for enhancers capable of regulating more than one promoter and to achieve allele-selective activation of human genes by targeting aTFs to SNPs embedded in distally located sequences. Our results broaden the potential applications of the epigenetic editing toolbox for research and therapeutics.
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    Therapeutic Base Editing of Human Hematopoietic Stem Cells
    (Springer Science and Business Media LLC, 2020-03-16) Zeng, Jing; Wu, Yuxuan; Ren, Chunyan; Bonanno, Jasmine; Shen, Anne H.; Shea, Devlin; Gehrke, Jason M.; Clement, Kendell; Luk, Kevin; Yao, Qiuming; Kim, Rachel; Wolfe, Scot A.; Manis, John; Pinello, Luca; Joung, Keith; Bauer, Daniel
    Base editing by nucleotide deaminases linked to programmable DNA-binding proteins represents a promising approach to permanently remedy blood disorders, although its application in engrafting hematopoietic stem cells (HSCs) remains unexplored. Here we purified A3A (N57Q)-BE3 protein for ribonucleoprotein (RNP) electroporation of human peripheral blood (PB) mobilized CD34+ hematopoietic stem and progenitor cells (HSPCs). We observed frequent on-target cytosine base edits at the BCL11A +58 erythroid enhancer with few indels. Fetal hemoglobin (HbF) induction in erythroid progeny after base editing or nuclease editing was similar. A single therapeutic base edit of the BCL11A enhancer prevented sickling and ameliorated globin chain imbalance in erythroid progeny from sickle cell disease (SCD) and β-thalassemia patient derived HSPCs respectively. Moreover efficient multiplex editing could be achieved with combined disruption of the BCL11A erythroid enhancer and correction of the HBB -28A>G promoter mutation. Finally base edits could be produced in multilineage-repopulating self-renewing human HSCs with high frequency as assayed in primary and secondary recipient animals resulting in potent HbF induction in vivo. Together these results demonstrate, to our knowledge for the first time, the potential of RNP base editing of human HSPCs as a feasible alternative to nuclease editing for HSC-targeted therapeutic genome modification.