he study revealed that DNA elements called transposons can affect a crucial shift in human development during the early stages.
Researchers at Sinai Health discovered that DNA elements called transposons which roam around the genome influence an important shift in human development rather than genes.
This new discovery challenges our understanding of the cryptic sequences of DNA, and offers new insights into their role in human disease.
Transposons are often compared to viruses, which hijack cells to propagate themselves. Dr. Miguel Ramalho-Santos is the senior co-author of the study. He is a Senior Investigator at Sinai Health's Lunenfeld-Tanenbaum Research Institute and Professor in the Department of Molecular Genetics of the University of Toronto.
The Canada 150 Research Chair for Developmental Epigenetics is held by Dr. Ramalho-Santos.
How DNA influences early development
The study published in Developmental Cell indicates that transposable element is critical to ensure human embryonic cell development proceeds normally during early stages, and not going back in history.
Researchers focused on transposable elements, also known as LINE-1 (long-interspersed nucleus element-1). Unlike genes which make up less than 2% of our genome, LINE-1 elements account for a staggering 20% of the genetic material within our cells. Some LINE-1 elements are able to move and amplify around the genome in order to insert themselves at new locations. They have earned the nickname "selfish DNA" because they can spread on their own and disrupt normal gene function.
Scientists believed that these elements were mostly damaging, sometimes causing havoc with the genome, and contributing to diseases ranging from cancer to neurological disorders.
Dr Juan Zhang, a co-author, postdoctoral researcher, and the person who led this research, found it initially intriguing that LINE-1 RNA message molecules are present in abundance in early embryos. RNA messages are transcribed by active parts of the genome, indicating LINE-1 elements in early embryos.
Why do we see transposons active in early embryos? This embryo is just starting to form. "Any dangerous insertion in the genome will be carried through the entire development of an individual", said Dr Zhang.
When Dr Zhang inhibited LINE-1 in cultured human ESCs, a reversal took place. They returned to the 8-cell stage. Each of the eight cells are identical and totipotent at this stage, and can develop into the embryo or placenta. ESCs are still able to form all fetal cell types, but they can no longer contribute to the placenta. This is the organ through which the embryo receives nutrition from the mother.
These LINE-1 molecules were found to act as a scaffold for organizing the DNA within the nucleus of the cell. They move chromosome 19, which contains crucial genes at the 8-cell level, to a region in the nucleus that silences gene activity. This ensures the embryo's ability to progress to the next stage without glitches.
"We demonstrate that LINE-1 regulates the gene expression at a critical turning point when the embryo begins to specialize its cell types for different functions. Our results show that this is not an accident, but a vital evolutionary process," said Dr Zhang.
This new role for LINE-1 elements is a departure from their usual behaviour, which involves jumping to different genomic locations to cause potentially harmful mutations. In this context, LINE-1 promotes only developmental progression. This is a unique effect that highlights their importance for early human growth.
This research is fundamental and has implications for the treatment of fertility problems as well as stem cell use in regenerative medicine. This work also reveals novel roles for LINE1, which can be explored within the contexts of disease where it is implicated. These include neurological disorders and cancer.
Dr Anne-Claude Gingras is the Director of LTRI, Vice President of Research for Sinai Health. She said: "This research highlights just how much there is left to learn about not only human development, but also these enigmatic DNA elements whose roles have only begun to emerge." I congratulated my colleagues for breaking new ground in human biology with this fascinating insight. I look forward to further discoveries when they continue their research.
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