基因敲除
基因
转基因
基因敲除
无意义介导的衰变
基因靶向
表型
斑马鱼
空等位基因
生物
遗传学
细胞生物学
核糖核酸
RNA剪接
作者
Zuwei Ma,Peipei Zhu,Hui Shi,Liwei Guo,Qinghe Zhang,Yanan Chen,Shuming Chen,Zhe Zhang,Jinrong Peng,Jun Chen
出处
期刊:Nature
[Springer Nature]
日期:2019-04-01
卷期号:568 (7751): 259-263
被引量:323
标识
DOI:10.1038/s41586-019-1057-y
摘要
The genetic compensation response (GCR) has recently been proposed as a possible explanation for the phenotypic discrepancies between gene-knockout and gene-knockdown1,2; however, the underlying molecular mechanism of the GCR remains uncharacterized. Here, using zebrafish knockdown and knockout models of the capn3a and nid1a genes, we show that mRNA bearing a premature termination codon (PTC) promptly triggers a GCR that involves Upf3a and components of the COMPASS complex. Unlike capn3a-knockdown embryos, which have small livers, and nid1a-knockdown embryos, which have short body lengths2, capn3a-null and nid1a-null mutants appear normal. These phenotypic differences have been attributed to the upregulation of other genes in the same families. By analysing six uniquely designed transgenes, we demonstrate that the GCR is dependent on both the presence of a PTC and the nucleotide sequence of the transgene mRNA, which is homologous to the compensatory endogenous genes. We show that upf3a (a member of the nonsense-mediated mRNA decay pathway) and components of the COMPASS complex including wdr5 function in GCR. Furthermore, we demonstrate that the GCR is accompanied by an enhancement of histone H3 Lys4 trimethylation (H3K4me3) at the transcription start site regions of the compensatory genes. These findings provide a potential mechanistic basis for the GCR, and may help lead to the development of therapeutic strategies that treat missense mutations associated with genetic disorders by either creating a PTC in the mutated gene or introducing a transgene containing a PTC to trigger a GCR.
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