Published today in Nature Communications, co-first author Yingxia Yan, PhD, and corresponding author Mario Halic, PhD, St. Jude Department of Structural Biology, demonstrate how cells recognize and defend themselves from invading transposons.
Transposons, DNA sequences that can self-replicate and move (jump) throughout the genome, are widespread and can affect cell survival if left unchecked. Cells control these “jumping genes” by silencing them, but little was known about how cells recognize and defend themselves from invading transposons. St. Jude Children’s Research Hospital scientists have answered that question, showing that cells sense abnormal RNA patterns produced by invading transposons and respond by activating pathways to silence them. Further, this process extends to any invasive DNA, provided it produces enough RNA disturbance for cells to detect. The study, published today in Nature Communications, offers insight into a genetic phenomenon that is at the center of diversity and evolution.
Led by corresponding author Mario Halic, PhD, St. Jude Department of Structural Biology, the researchers found that fission yeast cells silence invading transposons using two pathways. The first is RNA interference, which silences genes by destroying their messenger RNA. The second mechanism of silencing utilizes heterochromatin, a highly condensed form of DNA, which physically blocks transcription factors from engaging the DNA and, therefore, halts gene expression. Cells use both RNA interference and heterochromatin to detect and silence transposons, with recognition efficiency based on insertion location (where in the genome the transposon is) and copy number (how many copies of the transposon are there).
While the work was conducted in yeast, similar defensive mechanisms are also likely to exist in higher organisms, particularly in germline cells (sperm and eggs), which are particularly vulnerable to transposon-induced disruption.
“Every organism tries to defend itself from transposon invasion; they can proliferate uncontrollably and occupy large parts of the genome, slowing growth and negatively affecting gene expression,” Halic said. “Defensive systems like this are typically restricted to germline cells, where strong defense is essential. Otherwise, a transposon could propagate dramatically within just a few generations.”
Transposon silencing works for all invasive DNA
For their study, the researchers introduced an invasive transposon into cells and monitored as it jumped into different locations within the yeast genome. They then sequenced those locations and measured DNA copy number and RNA levels to see how efficiently they were silenced. Yeast strains that initially generated more RNA from the invading DNA were found to be more effective at detecting and silencing it, but the system that governs this is high-risk, high-reward, as the researchers note.
“Heterochromatin has a habit of spreading, silencing not only the transposon but also nearby genes,” Halic said. “Yeast cells that silence transposons this way initially grow slower, which is a disadvantage, but it becomes beneficial if transposons proliferate. This may explain why human adult cells use safer, more targeted systems instead of this broad silencing mechanism.”
Using RNA interference and heterochromatin, cells can quickly silence new transposons without recognizing their sequences, identifying them through disruptions in expression patterns instead. These findings offer key insights into how developing cells protect themselves from invasive genetic sequences.
“What excited us most was discovering that the cells don’t just silence transposons, they can silence any invasive DNA, as long as it produces enough RNA,” said co-first author Yinxia Yan, PhD, Department of Structural Biology. “This showed us that the cellular defense system is even smarter than we thought.”
Authors and funding
The study’s other first author is Luca Salvi, Ludwig-Maximilians-Universität München. The study was supported by the National Institutes of Health (1R01GM135599-01, 1R01GM141694-01 and R35GM158165) and the American Lebanese Syrian Associated Charities (ALSAC), the fundraising and awareness organization of St. Jude.
St. Jude Children's Research Hospital
St. Jude Children’s Research Hospital is leading the way the world understands, treats, and cures childhood catastrophic diseases. From cancer to life-threatening blood disorders, neurological conditions, and infectious diseases, St. Jude is dedicated to advancing cures and means of prevention through groundbreaking research and compassionate care. Through global collaborations and innovative science, St. Jude is working to ensure that every child, everywhere, has the best chance at a healthy future. To learn more, visit stjude.org, read St. Jude Progress, a digital magazine, and follow St. Jude on social media at @stjuderesearch.