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Large-scale discovery of potent, compact and lineage specific enhancers for gene therapy vectors [CUT&RUN]

ABSTRACT: Large-scale discovery of potent, compact and lineage specific enhancers for gene therapy vectors [CUT&RUN]

PROVIDER: PRJNA1057938 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR27369133_1.fastq.gz	Fastqsanger.gz
	SRR27369133_2.fastq.gz	Fastqsanger.gz
	SRR27369134_1.fastq.gz	Fastqsanger.gz
	SRR27369134_2.fastq.gz	Fastqsanger.gz

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Large-scale discovery of potent, compact and lineage specific enhancers for gene therapy vectors

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Large-scale discovery of potent, compact and lineage specific enhancers for gene therapy vectors [CUT&RUN]

Project description:Regulation of gene expression during cell development and differentiation is chiefly orchestrated by distal noncoding regulatory elements that precisely modulate cell selective gene activity. Gene therapy vectors rely on the cellular and context specificity of regulatory DNA elements to express therapeutic transgenes in the correct location and time. Here, we develop a straight-forward, one-shot approach to screen putative regulatory sequences identified in large-scale epigenomics profiling experiments for precise and programmable control of transgenes encoded within gene therapy viral vectors. We designed a library of 15,000 short sequences (~200bp) derived from a set of developmentally active DHS elements during human ex vivo erythropoiesis and cloned them into a GFP reporter lentiviral vector. In an erythroid progenitor cell line, these elements display a gradient of transcriptional enhancer activity, with some demonstrating equivalent activity to the canonical β-globin μLCR despite a 9-fold smaller size. We show that these elements are both highly cell type restricted and developmental stage specific both in vitro and in vivo. Finally, we replace the μLCR element with one of the novel short enhancers in a β-thalassemia lentiviral therapeutic vector and efficiently correct the thalassemic phenotype in patient-derived HSPCs. More broadly, our approach provides further insights into enhancer biology with wider implications into the development of highly cell type specific and efficacious viral vectors for human gene therapy.

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

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Compact engineered human mechanosensitive transactivation modules enable potent and versatile synthetic transcriptional control

Project description:Engineered transactivation domains (TADs) combined with programmable DNA binding platforms have revolutionized synthetic transcriptional control. Despite recent progress in programmable CRISPR/Cas-based transactivation (CRISPRa) technologies, the TADs used in these systems often contain poorly tolerated elements and/or are prohibitively large for many applications. Here we defined and optimized minimal TADs built from human mechanosensitive transcription factors (MTFs). We used these components to construct potent and compact multipartite transactivation modules (MSN, NMS, and eN3×9) and to build the CRISPR-dCas9 recruited enhanced activation module (CRISPR-DREAM) platform. We found that CRISPR-DREAM was specific, robust across mammalian cell types, and efficiently stimulated transcription from diverse regulatory loci. We also showed that MSN and NMS were portable across Type I, II, and V CRISPR systems, TALEs, and ZF proteins. Further, as proofs of concepts, we used dCas9-NMS to efficiently reprogram human fibroblasts into iPSCs and demonstrated that MTF TADs are efficacious and well tolerated in therapeutically important primary human cell types. Finally, we leveraged the compact and potent features of these engineered TADs to build new dual and all-in-one CRISPRa AAV systems. Altogether, these compact human TADs, fusion modules, and new delivery architectures should be valuable for synthetic transcriptional control in biomedical applications.

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