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PTC-bearing mRNA elicits a genetic compensation response via Upf3a and COMPASS components

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  • Zhipeng Ma

    (College of Life Sciences, Zhejiang University)

  • Peipei Zhu

    (College of Life Sciences, Zhejiang University)

  • Hui Shi

    (Zhejiang University
    Harvard Medical School)

  • Liwei Guo

    (College of Life Sciences, Zhejiang University)

  • Qinghe Zhang

    (College of Life Sciences, Zhejiang University)

  • Yanan Chen

    (College of Life Sciences, Zhejiang University)

  • Shuming Chen

    (College of Life Sciences, Zhejiang University)

  • Zhe Zhang

    (College of Life Sciences, Zhejiang University)

  • Jinrong Peng

    (Zhejiang University)

  • Jun Chen

    (College of Life Sciences, Zhejiang University)

Abstract

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.

Suggested Citation

  • Zhipeng Ma & Peipei Zhu & Hui Shi & Liwei Guo & Qinghe Zhang & Yanan Chen & Shuming Chen & Zhe Zhang & Jinrong Peng & Jun Chen, 2019. "PTC-bearing mRNA elicits a genetic compensation response via Upf3a and COMPASS components," Nature, Nature, vol. 568(7751), pages 259-263, April.
  • Handle: RePEc:nat:nature:v:568:y:2019:i:7751:d:10.1038_s41586-019-1057-y
    DOI: 10.1038/s41586-019-1057-y
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    Cited by:

    1. Juqi Zou & Satoshi Anai & Satoshi Ota & Shizuka Ishitani & Masayuki Oginuma & Tohru Ishitani, 2023. "Determining zebrafish dorsal organizer size by a negative feedback loop between canonical/non-canonical Wnts and Tlr4/NFκB," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    2. Min Zhou & Yuan Li & Xiao-Lei Yao & Jing Zhang & Sheng Liu & Hong-Rui Cao & Shuang Bai & Chun-Qu Chen & Dan-Xun Zhang & Ao Xu & Jia-Ning Lei & Qian-Zhuo Mao & Yu Zhou & De-Qiang Duanmu & Yue-Feng Guan, 2024. "Inorganic nitrogen inhibits symbiotic nitrogen fixation through blocking NRAMP2-mediated iron delivery in soybean nodules," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    3. Antonios Apostolopoulos & Naohiro Kawamoto & Siu Yu A. Chow & Hitomi Tsuiji & Yoshiho Ikeuchi & Yuichi Shichino & Shintaro Iwasaki, 2024. "dCas13-mediated translational repression for accurate gene silencing in mammalian cells," Nature Communications, Nature, vol. 15(1), pages 1-18, December.
    4. Federica Diofano & Karolina Weinmann & Isabelle Schneider & Kevin D Thiessen & Wolfgang Rottbauer & Steffen Just, 2020. "Genetic compensation prevents myopathy and heart failure in an in vivo model of Bag3 deficiency," PLOS Genetics, Public Library of Science, vol. 16(11), pages 1-24, November.

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