Developmental Accumulation of Gene Body and Transposon Non-CpG Methylation in the Zebrafish Brain

Samuel E Ross; Daniel Hesselson; Ozren Bogdanovic

doi:10.3389/fcell.2021.643603

Developmental Accumulation of Gene Body and Transposon Non-CpG Methylation in the Zebrafish Brain

Front Cell Dev Biol. 2021 Mar 4:9:643603. doi: 10.3389/fcell.2021.643603. eCollection 2021.

Authors

Samuel E Ross^{1

2}, Daniel Hesselson^{3

4}, Ozren Bogdanovic^{1

5}

Affiliations

¹ Genomics and Epigenetics Division, Garvan Institute of Medical Research, Sydney, NSW, Australia.
² Faculty of Medicine, St Vincent's Clinical School, University of New South Wales, Sydney, NSW, Australia.
³ Centenary Institute, The University of Sydney, Sydney, NSW, Australia.
⁴ Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, Australia.
⁵ School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, NSW, Australia.

Abstract

DNA methylation predominantly occurs at CG dinucleotides in vertebrate genomes; however, non-CG methylation (mCH) is also detectable in vertebrate tissues, most notably in the nervous system. In mammals it is well established that mCH is targeted to CAC trinucleotides by DNMT3A during nervous system development where it is enriched in gene bodies and associated with transcriptional repression. Nevertheless, the conservation of developmental mCH accumulation and its deposition by DNMT3A is largely unexplored and has yet to be functionally demonstrated in other vertebrates. In this study, by analyzing DNA methylomes and transcriptomes of zebrafish brains, we identified enrichment of mCH at CAC trinucleotides (mCAC) at defined transposon motifs as well as in developmentally downregulated genes associated with developmental and neural functions. We further generated and analyzed DNA methylomes and transcriptomes of developing zebrafish larvae and demonstrated that, like in mammals, mCH accumulates during post-embryonic brain development. Finally, by employing CRISPR/Cas9 technology, we unraveled a conserved role for Dnmt3a enzymes in developmental mCAC deposition. Overall, this work demonstrates the evolutionary conservation of developmental mCH dynamics and highlights the potential of zebrafish as a model to study mCH regulation and function during normal and perturbed development.

Keywords: DNA methylation; brain; nervous system; repetitive elements; zebrafish.