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Genetic compensation prevents myopathy and heart failure in an in vivo model of Bag3 deficiency

Author

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  • Federica Diofano
  • Karolina Weinmann
  • Isabelle Schneider
  • Kevin D Thiessen
  • Wolfgang Rottbauer
  • Steffen Just

Abstract

Mutations in the molecular co-chaperone Bcl2-associated athanogene 3 (BAG3) are found to cause dilated cardiomyopathy (DCM), resulting in systolic dysfunction and heart failure, as well as myofibrillar myopathy (MFM), which is characterized by protein aggregation and myofibrillar disintegration in skeletal muscle cells. Here, we generated a CRISPR/Cas9-induced Bag3 knockout zebrafish line and found the complete preservation of heart and skeletal muscle structure and function during embryonic development, in contrast to morpholino-mediated knockdown of Bag3. Intriguingly, genetic compensation, a process of transcriptional adaptation which acts independent of protein feedback loops, was found to prevent heart and skeletal muscle damage in our Bag3 knockout model. Proteomic profiling and quantitative real-time PCR analyses identified Bag2, another member of the Bag protein family, significantly upregulated on a transcript and protein level in bag3-/- mutants. This implied that the decay of bag3 mutant mRNA in homozygous bag3-/- embryos caused the transcriptional upregulation of bag2 expression. We further demonstrated that morpholino-mediated knockdown of Bag2 in bag3-/- embryos evoked severe functional and structural heart and skeletal muscle defects, which are similar to Bag3 morphants. However, Bag2 knockdown in bag3+/+ or bag3+/- embryos did not result in (cardio-)myopathy. Finally, we found that inhibition of the nonsense-mediated mRNA decay (NMD) machinery by knockdown of upf1, an essential NMD factor, caused severe heart and skeletal muscle defects in bag3-/- mutants due to the blockade of transcriptional adaptation of bag2 expression. Our findings provide evidence that genetic compensation might vitally influence the penetrance of disease-causing bag3 mutations in vivo.Author summary: One form of genetic compensation is described as transcriptional adaptation of gene expression triggered by deleterious gene mutations. Although the precise molecular mechanism that induces genetic compensation needs to be defined, it represents a powerful biological phenomenon that warrants genetic robustness. We find that antisense-mediated knockdown of Bag3 in zebrafish embryos causes heart failure and myopathy. By contrast, CRISPR/Cas9-induced depletion of Bag3 does not result in the abrogation of heart and skeletal muscle function in zebrafish embryos. We find here that transcriptional activation of the Bag family member bag2 is capable of restoring heart and skeletal muscle function in bag3 mutant embryos, whereas this compensatory mechanism is not present in the bag3 morphants. Furthermore, we show that nonsense-mediated decay of bag3 mRNA is the molecular trigger for the compensatory upregulation of bag2. Our study provides evidence that genetic compensation via transcriptional adaptation is a vital modulator of disease peculiarity and penetrance in bag3 mutant zebrafish and that this biological phenomenon might also be active in certain human BAG3 mutation carriers.

Suggested Citation

  • 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.
  • Handle: RePEc:plo:pgen00:1009088
    DOI: 10.1371/journal.pgen.1009088
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    1. Ross N. W. Kettleborough & Elisabeth M. Busch-Nentwich & Steven A. Harvey & Christopher M. Dooley & Ewart de Bruijn & Freek van Eeden & Ian Sealy & Richard J. White & Colin Herd & Isaac J. Nijman & Fr, 2013. "A systematic genome-wide analysis of zebrafish protein-coding gene function," Nature, Nature, vol. 496(7446), pages 494-497, April.
    2. Mohamed A. El-Brolosy & Zacharias Kontarakis & Andrea Rossi & Carsten Kuenne & Stefan Günther & Nana Fukuda & Khrievono Kikhi & Giulia L. M. Boezio & Carter M. Takacs & Shih-Lei Lai & Ryuichi Fukuda &, 2019. "Genetic compensation triggered by mutant mRNA degradation," Nature, Nature, vol. 568(7751), pages 193-197, April.
    3. Andrea Rossi & Zacharias Kontarakis & Claudia Gerri & Hendrik Nolte & Soraya Hölper & Marcus Krüger & Didier Y. R. Stainier, 2015. "Genetic compensation induced by deleterious mutations but not gene knockdowns," Nature, Nature, vol. 524(7564), pages 230-233, August.
    4. 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.
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