Researchers at Sinai Health have discovered that DNA elements known as transposons, which may travel throughout the genome, control a crucial stage in early human development instead of human genes.
Their astounding discovery casts doubt on prior knowledge of these mysterious DNA sequences and provides fresh insight into their functions in human development and illness.
People tend to think of transposons as akin to viruses where they hijack our cells for the sole purpose of propagating themselves.”
Dr. Miguel Ramalho-Santos, Study Senior Co-Author and Professor, Department of Molecular Genetics, University of Toronto
Ramalho-Santos is also a Senior Investigator at the Lunenfeld-Tanenbaum Research Institute (LTRI), part of Sinai Health.
“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.
According to their research, which was published in the journal Developmental Cell, transposable elements are essential to ensuring that human embryonic cells develop appropriately during the early stages of life rather than regressing.
The transposable elements known as LINE-1, or long interspersed nuclear element-1, were the main focus of the study. The LINE-1 elements make up an astounding 20% of the genetic material in the cells, in contrast to human genes, which make up less than 2% of genome.
Certain LINE-1 elements can amplify and spread throughout the genome, settling in new places. They have been dubbed “selfish DNA” because they spread spontaneously in a way that can interfere with regular gene functioning.
For many years, scientists thought these atoms were primarily bad, sometimes causing chaos in the genome and causing a range of illnesses, from cancer to neurological disorders to hemophilia.
The abundance of LINE-1 RNA signals in the early embryo originally intrigued Dr. Juan Zhang, a Senior Co-Author and Postdoctoral Scholar who led the study. LINE-1 elements are activated during these crucial early phases, as evidenced by the transcription of RNA message molecules from active regions of the genome.
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.”
Dr. Juan Zhang, Senior Co-Author and Postdoctoral Scholar, University of Toronto
Cultured human embryonic stem cells (ESCs) underwent a reversal when Dr. Zhang suppressed LINE-1 expression, returning them to the earlier 8-cell stage. Each of the eight cells is now totipotent, meaning it can develop into both the embryo and the placenta.
ESCs can still generate all of the fetal cells beyond this point, but their ability to contribute to the placenta, which is how the embryo receives nutrition from the mother, decreases.
Subsequent research revealed that these LINE-1 message molecules serve as a framework to arrange the DNA in the nucleus' three-dimensional space. To ensure the embryo can proceed to later stages without any problems, they assist in moving chromosome 19, which contains essential genes for the 8-cell stage, to a gene-silencing region of the nucleus.
“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.
This unexpected function of LINE-1 elements adds to the surprises because it differs from their usual behavior of leaping to new genomic sites and creating potentially dangerous alterations. Rather, in this crucial situation, LINE-1 components only promote developmental advancement, a special function that emphasizes their significance in the early stages of human development.
This basic study significantly impacts the application of stem cells in regenerative medicine and fertility treatments. Furthermore, the work reveals new functions for LINE1, which can now be investigated in the illness scenarios in which it has been implicated, ranging from cancer to neurological disorders.
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.”
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