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Researchers at the Garvan Institute of Medical Research have discovered a new form of DNA modification in the genome of the zebrafish, a vertebrate animal that shares an evolutionary ancestor with humans some 400 million years ago.
Dr Ozren Bogdanovic and his team found that unusually high levels of DNA repeats of the “TGCT” sequence in the zebrafish genome undergo a modification called methylation, which can change the shape or activity of the surrounding DNA. The study, published in Research on nucleic acids and conducted in collaboration with Queen Mary University of London, could lead to the development of new experimental models for studying the impact of DNA modifications on human development and disease.
“We have revealed a new form of DNA methylation in zebrafish at TGCT repeats and, more importantly, the enzyme that makes the modification,” says Dr. Biomolecular Sciences, UNSW Sydney. “These findings open up new possibilities in studying the epigenome – the additional layer of instructions on DNA that change the way genes are read – and understanding how it can be clinically relevant.”
Hidden signatures
All species that have DNA – from plants to humans – also modify it by attacking molecules called methyl groups.
“DNA methylation is vital for cellular function, as it controls which genes are turned on and off,” explains the article’s first author, PhD student Sam Ross. “This is why the cells in our body can perform very different functions, despite having nearly identical DNA.”
There are four “base” letters that make up DNA: C, G, T, and A. In vertebrates, methylation occurs primarily where the letter G follows a C (“CG”), but there are some exceptions. One example is methylation at non-CG sites in human brain cells, the aberrations of which have been linked to Rett syndrome, a genetic disorder that impairs growth, movement, and speech in children.
To further investigate non-CG methylation, the researchers conducted a comprehensive genome profiling of zebrafish, a vertebrate organism that is a distant evolutionary relative of humans and shares 70% of our genes, making it a useful model for the study of human genes effects.
The team found that methylation occurred where the “TGCT” sequence appeared multiple times, close together.
“We were fascinated to see that methylation levels at TGCT repeats were higher than any previously observed non-CG methylation in most adult vertebrate tissues,” says Dr. Bogdanovic. “Furthermore, this methylation was present at high levels in the sperm and egg, absent in the fertilized egg, and then reappeared in the growing embryo, reaching its highest levels in adult tissues such as the brain and gonads. we have yet to do so. reveal how this modification changes gene expression, we believe that TGCT methylation is linked to the “awakening” of the embryonic genome in zebrafish. “
New potential for studying the disease
The researchers also revealed that the Dnmt3ba enzyme was responsible for the methylation of TGCT repeats in the zebrafish genome.
“While it is unclear whether a similar change occurs in animals more broadly, our finding in zebrafish is significant, because it means we can begin to selectively manipulate this atypical form of methylation in a model organism. It means we can change. Dnmt3ba levels in looks at what happens when we only remove one form of methylation, but not another, “says Dr. Bogdanovic.
“This could greatly facilitate our understanding of how changes in atypical methylation patterns affect specific tissues such as the brain, to gain further insights into the molecular mechanisms of neurodevelopmental disorders,” says Dr. Bogdanovic.
“We hope our results will help us develop new experimental models that can be used to study epigenetics in a way that has not been possible until now.”
This research was supported by the Australian Research Council (DP190103852).
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