Once thought of as “junk DNA” because they were not believed to genetically correlate to biological functions, the world’s geneticists may want to reconsider the importance of certain noncoding RNA molecules in how humans and other primates develop.
Top stem cell scientists at Montana State University and Stanford University have shown that certain noncoding RNA molecules, which are genetic remnants of an ancient virus, play a critical role in balancing decisions in early human development – namely pluripotency of early stem cells, a genetic state that enables them to modulate the gamut of human developmental decisions and timing. The findings were detailed in a paper published online today in the journal Nature Genetics.
Renee Reijo Pera, who is vice president for research and economic development at Montana State University and also heads up a stem cell research laboratory, is the senior author of the work. Vittorio Sebastiano, an assistant professor of obstetrics and gynecology, and Jens Durruthy-Durruthy, a postdoctoral scholar, both of the Stanford School of Medicine, are co-first authors. Reijo Pera, who came to MSU in 2014, after serving as director of the Stanford’s Center for Human Pluripotent Stem Cell Research and Education and the Center for Reproductive and Stem Cell Biology, is regarded as one of the world’s top authorities on embryonic stem cells.
“This research is transforming our fundamental understanding of these molecules, and their role in how stem cells impact a whole array of human developmental decisions and timing,” Reijo Pera said.
The paper traces several of these noncoding RNA molecules to the remnants of an ancient viral infection in nonhuman primates. Genetic traces of these viral materials have evolved to be essential ingredients to allow a fertilized human egg to initiate an embryo’s pluripotency and ability to develop into all different human cells and tissues. In their study, researchers showed they could halt that developmental process by blocking these noncoding RNA molecules.
Evidence of a link between these noncoding RNA molecules and the onset of pluripotency for a fertilized egg marks a major step in recently emerging understanding of noncoding RNA as among primate-specific genomes tied to important biological functions. Its role appears to hinge on the viral residue contained in these RNA molecules. This research built off of another study that was published earlier this year in Nature and was co-authored by Reijo Pera and colleagues at from Stanford. That research found that newly formed human embryos contain viral particles that stem from similar remnant genetic material.
“We’re starting to accumulate evidence that these viral sequences, which originally may have threatened the survival of our species, were co-opted by our genomes for their own benefit,” Sebastiano told the Stanford News Center. “In this manner, they may even have contributed species-specific characteristics and fundamental cell processes, even in humans.”
The pluripotent ability of stem cells has offered biomedical researchers many opportunities to explore how certain functions can be controlled, an area of research of great interest to the pharmaceutical industry for the potential development of drugs and other medical therapies. And scientists can prompt some fully developed human cells to become pluripotent by exposing them to proteins known to be present in the very early human embryo. But how the process of becoming pluripotent unfolds at the molecular level is less clear.
The team used a new, highly specific DNA and RNA sequencing and editing technique called CRISPR to identify and analyze the role of RNA molecules that do not express proteins but rather impact the expression in other genes, molecules that are known as long intergenic noncoding RNA, or lincRNA. Sebastiano, Durruthy-Durruthy, Reijo Pera and their colleagues identified more than 2,000 previously unknown lincRNA sequences, 146 of which are specifically expressed in embryonic stem cells. They then focused on 23 that were among the most highly expressed sequences. Thirteen of these so-called HPAT1-23 were comprised almost exclusively of genetic material that evolved from an ancient human infection by a virus called HERV-H.
“The use of CRISPR technology allowed us to examine the function of individual viral-repeat containing genes,” Reijo Pera said. “What we found surprised us: Individual sequences are important for tuning our development.”
Because HERV-H was a retrovirus – one that infects and passes along its genetics to the host – bits of its genetic material, like those of countless other viruses, became assimilated into the evolving human genome.
The new study found that three molecules in particular – HPAT2, HPAT3 and HPAT5 – were expressed only in the inner cell mass of the embryonic blastocyst, the two-celled embryo that becomes the developing fetus. Blocking their expression had detrimental effect on human development both in the embryo and in stem cell populations in vitro. In fact, the researchers also showed that the three genes also need to be present if adult cells are to be transformed into induced pluripotent stem cells.
“This is the first time that these virally derived RNA molecules have been shown to be directly involved with and necessary for vital steps of human development,” Sebastiano told the Stanford News Center. “What’s really interesting is that these sequences are found only in primates, raising the possibility that their function may have contributed to unique characteristics that distinguish humans from other animals.”
Reijo Pera said new findings add to the already-profound legacy of stem cell research, a field in which MSU is now a growing player.
“We think that much of human development, and perhaps disease, may be linked to these human specific noncoding RNAs, which comprise a major portion of our genes,” Reijo Pera said. “It’s wonderful to be a part of this greater community of stem cell scientists and wonderful to know that Montana State University is going to add a new generation of scientists to carry forward our understanding of how stem cells carry on their critical function.”
Renee Reijo Pera, email@example.com or (406) 994-2891