Enhanced mitochondrial DNA editing in mice using nuclear-exported TALE-linked deaminases and nucleases.

IF 12.3 1区 生物学 Q1 Agricultural and Biological Sciences
Seonghyun Lee, Hyunji Lee, Gayoung Baek, Eunji Namgung, Joo Min Park, Sanghun Kim, Seongho Hong, Jin-Soo Kim
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引用次数: 0

Abstract

We present two methods for enhancing the efficiency of mitochondrial DNA (mtDNA) editing in mice with DddA-derived cytosine base editors (DdCBEs). First, we fused DdCBEs to a nuclear export signal (DdCBE-NES) to avoid off-target C-to-T conversions in the nuclear genome and improve editing efficiency in mtDNA. Second, mtDNA-targeted TALENs (mitoTALENs) are co-injected into mouse embryos to cleave unedited mtDNA. We generated a mouse model with the m.G12918A mutation in the MT-ND5 gene, associated with mitochondrial genetic disorders in humans. The mutant mice show hunched appearances, damaged mitochondria in kidney and brown adipose tissues, and hippocampal atrophy, resulting in premature death.

Abstract Image

Abstract Image

利用核输出的 TALE 链接脱氨酶和核酸酶加强小鼠线粒体 DNA 编辑。
我们介绍了两种利用 DddA 衍生胞嘧啶碱基编辑器(DdCBEs)提高小鼠线粒体 DNA(mtDNA)编辑效率的方法。首先,我们将 DdCBE 与核输出信号(DdCBE-NES)融合,以避免核基因组中的脱靶 C-T 转换,提高 mtDNA 的编辑效率。其次,将mtDNA靶向TALENs(mitoTALENs)联合注射到小鼠胚胎中,裂解未编辑的mtDNA。我们生成了一种具有 MT-ND5 基因 m.G12918A 突变的小鼠模型,这种突变与人类线粒体遗传疾病有关。突变小鼠表现出驼背、肾脏和棕色脂肪组织中的线粒体受损以及海马萎缩,导致过早死亡。
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来源期刊
Genome Biology
Genome Biology BIOTECHNOLOGY & APPLIED MICROBIOLOGY-GENETICS & HEREDITY
CiteScore
25.50
自引率
3.30%
发文量
0
审稿时长
14 weeks
期刊介绍: Genome Biology is a leading research journal that focuses on the study of biology and biomedicine from a genomic and post-genomic standpoint. The journal consistently publishes outstanding research across various areas within these fields. With an impressive impact factor of 12.3 (2022), Genome Biology has earned its place as the 3rd highest-ranked research journal in the Genetics and Heredity category, according to Thomson Reuters. Additionally, it is ranked 2nd among research journals in the Biotechnology and Applied Microbiology category. It is important to note that Genome Biology is the top-ranking open access journal in this category. In summary, Genome Biology sets a high standard for scientific publications in the field, showcasing cutting-edge research and earning recognition among its peers.
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