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An epigenetic mechanism for cavefish eye degeneration

Nature Ecology & Evolution volume 2, pages 1155–1160 (2018)Cite this article

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Abstract

Coding and non-coding mutations in DNA contribute significantly to phenotypic variability during evolution. However, less is known about the role of epigenetics in this process. Although previous studies have identified eye development genes associated with the loss-of-eyes phenotype in the Pachón blind cave morph of the Mexican tetra Astyanax mexicanus, no inactivating mutations have been found in any of these genes. Here, we show that excess DNA methylation-based epigenetic silencing promotes eye degeneration in blind cave A. mexicanus. By performing parallel analyses in A. mexicanus cave and surface morphs, and in the zebrafish Danio rerio, we have discovered that DNA methylation mediates eye-specific gene repression and globally regulates early eye development. The most significantly hypermethylated and downregulated genes in the cave morph are also linked to human eye disorders, suggesting that the function of these genes is conserved across vertebrates. Our results show that changes in DNA methylation-based gene repression can serve as an important molecular mechanism generating phenotypic diversity during development and evolution.

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Fig. 1: Eye phenotypes in A. mexicanus surface fish and cavefish, and D. rerio wild-type and dnmt3bb.1y258 mutants.
Fig. 2: Gene expression changes in cave versus surface fish morphs of A. mexicanus.
Fig. 3: Eye phenotype and associated gene expression changes in wild-type and DNA methylation-deficient D. rerio.
Fig. 4: Partial rescue of cavefish eyes by Aza-mediated inhibition of eye DNA methylation.

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Acknowledgements

We thank members of the Weinstein and Jeffery laboratories for support, help and suggestions. We thank staff at the NICHD's Molecular Genomics Laboratory for bisulfite and RNA-Seq assistance. We also thank members of the zebrafish and cavefish communities for sharing reagents and protocols. We thank K. Sampath for comments on the manuscript. We thank S. McGaugh for suggestions on cavefish sequence alignments and M. Goll for providing the zebrafish tet2,3 double mutant line. Work in the Weinstein and Jeffery laboratories is supported by the intramural programme of the NICHD and by R01EY024941, respectively.

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Authors and Affiliations

  1. Division of Developmental Biology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, Bethesda, MD, USA

    Aniket V. Gore, Kelly A. Tomins, Daniel Castranova, Andrew E. Davis, Amy Parkhurst & Brant M. Weinstein

  2. Molecular Genomics Laboratory, Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, Bethesda, MD, USA

    James Iben

  3. Department of Biology, University of Maryland, College Park, MD, USA

    Li Ma & William R. Jeffery

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  1. Aniket V. Gore
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Contributions

A.V.G. and B.M.W. designed the study with input from K.A.T. and W.R.J. A.V.G. and K.A.T. performed the experiments with help from L.M., D.C. and A.E.D. J.I. analysed the sequencing data. D.C. and A.E.D. provided fish husbandry support. A.V.G. and B.M.W. wrote the manuscript with input from all authors.

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Correspondence to Aniket V. Gore or Brant M. Weinstein.

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Supplementary information

Supplementary Figures

Supplementary Figures 1–7

Reporting Summary

Supplementary Data 1

Differentially up and down regulated genes from surface and cavefish eyes at 54 hpf by RNA seq analysis

Supplementary Data 2

Cavefish genes with significant promoter hypermethylation and reduced gene expression

Supplementary Data 3

Cavefish genes with substantial promoter hypermethylation and reduced gene expression and their linked human disease phenotypes

Supplementary Data 4

Primer sequences used in this study

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Gore, A.V., Tomins, K.A., Iben, J. et al. An epigenetic mechanism for cavefish eye degeneration. Nat Ecol Evol 2, 1155–1160 (2018). https://doi.org/10.1038/s41559-018-0569-4

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