Researchers shed new light on role of DNA in human development
Toronto [Canada], October 15 (ANI): Sinai Health researchers discovered that DNA elements known as transposons, which may roam around the genome, influence a vital shift in early human development, rather than our genes.
This novel discovery calls into question our previous understanding of these cryptic DNA sequences, offering new insight into their involvement in human development and disease.
"People tend to think of transposons as akin to viruses where they hijack our cells for the sole purpose of propagating themselves," says study's senior co-author Dr. Miguel Ramalho-Santos, Senior Investigator at the Lunenfeld-Tanenbaum Research Institute (LTRI), part of Sinai Health, and Professor at the Department of Molecular Genetics at the University of Toronto.
"But here we have discovered that these elements are not mere genomic parasites but are essential for early development," said Dr. Ramalho-Santos, who holds the Canada 150 Research Chair in Developmental Epigenetics.
Their study, published in the journal Developmental Cell, indicates that transposable elements are critical to ensure that human embryonic cells progress normally through early development, rather than going back in time.
Their study, published in the journal Developmental Cell, indicates that transposable elements are critical to ensure that human embryonic cells progress normally through early development, rather than going back in time.
The researchers focussed on the transposable elements known as LINE-1, for long-interspersed nuclear element-1. Unlike our genes, which compose less than 2 per cent of our genome, the LINE-1elements comprise a staggering 20 per cent of the genetic material in our cells. Some LINE-1 elements can amplify and move around the genome, inserting themselves in new locations. Because they spread of their own accord in a way that can disrupt normal gene functions, this has earned them the moniker of "selfish DNA".
For years, scientists believed these elements were mostly harmful, occasionally wreaking havoc in the genome and contributing to a variety of diseases, from haemophilia to neurological disorders and cancer.
Dr Juan Zhang, a senior co-author and postdoctoral fellow who spearheaded the research, initially found it intriguing that LINE-1 RNA messages are abundant in early embryos. RNA message molecules are transcribed from parts of the genome that are active, indicating that LINE-1 elements are switched on in these critical early stages.
Dr Juan Zhang, a senior co-author and postdoctoral fellow who spearheaded the research, initially found it intriguing that LINE-1 RNA messages are abundant in early embryos. RNA message molecules are transcribed from parts of the genome that are active, indicating that LINE-1 elements are switched on in these critical early stages.
"If transposons are bad and dangerous, why do we see them active in the early embryo? This is an embryo that's just beginning its formation. Any dangerous insertion into the genome at this point is going to be propagated throughout the rest of the development of the individual," said Dr Zhang.
When Dr Zhang inhibited LINE-1 expression in cultured human embryonic stem cells (ESCs), a reversal occurred, taking them back to the more primitive 8-cell stage. At this point, each of the eight cells is identical and totipotent, capable of developing into both the embryo and placenta. However, beyond this stage, while ESCs can still form all fetal cells, they become less and less able to contribute to the placenta, through which the embryo receives nutrients from the mother.
When Dr Zhang inhibited LINE-1 expression in cultured human embryonic stem cells (ESCs), a reversal occurred, taking them back to the more primitive 8-cell stage. At this point, each of the eight cells is identical and totipotent, capable of developing into both the embryo and placenta. However, beyond this stage, while ESCs can still form all fetal cells, they become less and less able to contribute to the placenta, through which the embryo receives nutrients from the mother.
Further experiments showed that these LINE-1 message molecules act as a scaffold to organize the DNA in the 3D space of the cell's nucleus. They help move chromosome 19--home to crucial genes for the 8-cell stage--to a gene-silencing region of the nucleus, ensuring the embryo can progress to subsequent stages without a glitch.
"We show that LINE-1 regulates gene expression at a crucial turning point where the embryo starts to specialize its cells for various functions. Our results indicate that this not an accidental occurrence but a vital evolutionary mechanism," said Dr Zhang.
"We show that LINE-1 regulates gene expression at a crucial turning point where the embryo starts to specialize its cells for various functions. Our results indicate that this not an accidental occurrence but a vital evolutionary mechanism," said Dr Zhang.
Adding to the surprises, this new role of LINE-1 elements deviates from their typical behaviour of jumping to new genomic locations and thereby causing potentially harmful mutations. Instead, in this critical context, LINE-1 elements exclusively foster developmental progression, a unique action that underscores their importance in early human growth.
This fundamental research has important implications for fertility treatments and the use of stem cells in regenerative medicine. Moreover, this work unveils novel roles for LINE1 that can now be explored in the disease contexts where it has been implicated, from neurological disorders to cancer.
Dr Anne-Claude Gingras, Director of LTRI and Vice President of Research for Sinai Health has said, "This research underscores just how much more there is to learn, not only about human development but also about these enigmatic genome elements whose roles are only beginning to emerge. I congratulate my colleagues on breaking new ground with this fascinating insight into human biology, and I eagerly anticipate further discoveries as they continue their work." (ANI)
Dr Anne-Claude Gingras, Director of LTRI and Vice President of Research for Sinai Health has said, "This research underscores just how much more there is to learn, not only about human development but also about these enigmatic genome elements whose roles are only beginning to emerge. I congratulate my colleagues on breaking new ground with this fascinating insight into human biology, and I eagerly anticipate further discoveries as they continue their work." (ANI)
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