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Nat Commun ; 12(1): 4902, 2021 08 12.
Artigo em Inglês | MEDLINE | ID: mdl-34385461


Efficient and precise base editors (BEs) for C-to-G transversion are highly desirable. However, the sequence context affecting editing outcome largely remains unclear. Here we report engineered C-to-G BEs of high efficiency and fidelity, with the sequence context predictable via machine-learning methods. By changing the species origin and relative position of uracil-DNA glycosylase and deaminase, together with codon optimization, we obtain optimized C-to-G BEs (OPTI-CGBEs) for efficient C-to-G transversion. The motif preference of OPTI-CGBEs for editing 100 endogenous sites is determined in HEK293T cells. Using a sgRNA library comprising 41,388 sequences, we develop a deep-learning model that accurately predicts the OPTI-CGBE editing outcome for targeted sites with specific sequence context. These OPTI-CGBEs are further shown to be capable of efficient base editing in mouse embryos for generating Tyr-edited offspring. Thus, these engineered CGBEs are useful for efficient and precise base editing, with outcome predictable based on sequence context of targeted sites.

Sistemas CRISPR-Cas , Citidina Desaminase/metabolismo , Edição de Genes/métodos , Aprendizado de Máquina , Uracila-DNA Glicosidase/metabolismo , Animais , Sequência de Bases , Sítios de Ligação/genética , Caenorhabditis elegans/genética , Códon/genética , Citidina Desaminase/genética , Escherichia coli/genética , Feminino , Biblioteca Gênica , Células HEK293 , Humanos , Camundongos , Reprodutibilidade dos Testes , Uracila-DNA Glicosidase/genética
Exp Gerontol ; 97: 89-96, 2017 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-28750751


Tea includes puer tea, black tea, green tea and many others. By using model organism Caenorhabditis elegans, the anti-aging and anti-oxidation effects of tea water extract were systemically examined in this study. We found that water extract of puer tea, black tea and green tea all increased the lifespan of worms, postponed Aß-induced progressive paralysis in Alzheimer's disease transgenic worms, and improved the tolerance of worms to the oxidative stress induced by heavy metal Cr6+. Moreover, the anti-oxidation effects of tea water extract at low concentration were different among 4 kinds of brands of green tea. The underlying mechanisms were further explored using genetically manipulated-mutant worms. The anti-oxidative stress effects of green tea water extract depend on the dietary restriction and germline signaling pathways, but not the FOXO and mitochondrial respiratory chain signals. Therefore, tea water extract provides benefits of anti-aging, anti-AD and anti-oxidation.

Antioxidantes/farmacologia , Caenorhabditis elegans/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Extratos Vegetais/farmacologia , Chá/química , Animais , Animais Geneticamente Modificados , Caenorhabditis elegans/fisiologia , Fatores de Transcrição Forkhead/metabolismo , Oxirredução , Transdução de Sinais/efeitos dos fármacos