![The images show the inside of the cell nucleus at an 8-cell stage (left) and at a later stage (right). Chromosome 19 is shown in red whereas the nucleolus containing the gene-silencing machinery is in green. One can see close intermingling of chromosome 19 and the gene-silencing machinery at the later developmental stage (right). Inhibition of LINE-1 reverses the cells to an earlier stage as evident by less green/red overlap on the left. [Dr. Juan Zhang and Dr. Miguel Ramalho-Santos]](https://www.genengnews.com/wp-content/uploads/2024/10/low-res-5.jpeg "The images show the inside of the cell nucleus at an 8-cell stage (left) and at a later stage (right). Chromosome 19 is shown in red whereas the nucleolus containing the gene-silencing machinery is in green. One can see close intermingling of chromosome 19 and the gene-silencing machinery at the later developmental stage (right). Inhibition of LINE-1 reverses the cells to an earlier stage as evident by less green/red overlap on the left. [Dr. Juan Zhang and Dr. Miguel Ramalho-Santos]")
Researchers at Sinai Health have found that a critical transition in early human development is regulated not by our genes, but by DNA elements called transposons that can move around the genome. The discovery challenges previous understanding of these DNA segments, indicating that transposable elements (TEs) are critical to ensure that human embryonic cells progress normally through early development, rather than going back in time. The research may also shed new light on the roles that transposable elements play in disease, and could be relevant to fertility treatments and the use of stem cells in regenerative medicine.
“People tend to think of transposons as akin to viruses where they hijack our cells for the sole purpose of propagating themselves,” said Miguel Ramalho-Santos, PhD, 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.” Ramalho-Santos holds the Canada 150 Research Chair in Developmental Epigenetics, and is co-senior author of the team’s published paper in Developmental Cell, which is titled “LINE1 and PRC2 control nucleolar organization and repression of the 8C state in human ESCs.”
For their study the researchers focused on transposable elements known as LINE-1 (long interspersed nuclear element-1). Unlike our genes, which represent less than 2% of our genome, LINE-1 elements comprise 20% 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, they’ve been termed “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 hemophilia to neurological disorders and cancer.
However, as the authors noted in their newly reported work, previous studies have indicated that these elements may also play a role in development. “We and others have shown that the expression of the largest family of mammalian transposable elements (TEs), long interspersed nuclear element 1 (LINE1), is essential for mouse embryonic stem cell (mESC) self-renewal and pre-implantation development,” the team stated.
Co-senior author Juan Zhang, PhD, a postdoctoral fellow who spearheaded the research, initially found it intriguing that LINE-1 RNA messages are abundant in early embryo. 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,” Zhang said.
When Zhang inhibited LINE-1 expression in cultured human embryonic stem cells (hESCs) 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. “Here, we show that the family of long interspersed nuclear element 1 (LINE1) transposons prevents the reversion of naive human embryonic stem cells (hESCs) to 8-cell-like cells (8CLCs),” the team commented.
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 (chr19)—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. “Our results further reveal a remarkably dynamic behavior of chromosome 19 (chr19) in the transition between hESCs and 8CLCs,” they noted. “Our data further indicate that chr19 is a focal point for regulation of the 8C program and displays a remarkably dynamic localization relative to the nucleolus between 8CLCs and naive hESCs.”
Zhang added, “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.”
Adding to the surprises, this new role of LINE-1 elements deviates from their typical behavior 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. “Our results indicate that a fundamental transition at the onset of early mammalian development is regulated by the expression of LINE1 elements,” the team stated in their paper.
As well as presenting relevance for fertility treatments and the use of stem cells in regenerative medicine, the newly reported results unveil novel roles for LINE1 that can now be explored in the disease contexts where it has been implicated, from neurological disorders to cancer.
