Key repeater molecule that governs genetic memory discovered

By Jessica Hall 

How can environmental happenstance make its way into our genetic inheritance? The question of how epigenetic influence actually happens has been a tough nut to crack, even with sophisticated chemical testing and microscopy at our disposal. Now a new (paywalled) report from Tel Aviv University has given us a glimpse at the process by which outward influences can echo across generations. The short story is that C. elegans, science’s favorite flatworm, uses RNA like an epigenetic Wi-Fi repeater.

The RNA hypothesis

Central to the Tel Aviv team’s experiment was the idea that there must be some system by which the genome could physically acknowledge outwardly events. Whatever was happening outside the individual, they reasoned, it had to get into the heritable material somehow, past all the error-correction mechanisms and other cellular defenses.

New RNAi episodes extend the duration of heritable epigenetic effects. Image credit: study authors.

The medium of transmission that the team chose to investigate was RNA: an important genetic messenger molecule, common to all life on Earth. Their experiments showed that certain genes, which the scientists named “MOTEK” (Modified Transgenerational Epigenetic Kinetics), were responsible for turning epigenetic transmissions on and off. “We discovered how to manipulate the transgenerational duration of epigenetic inheritance in worms by switching ‘on’ and ‘off’ the small RNAs that worms use to regulate genes,” said Dr. Oded Rechavi, lead author of the report. “These switches are controlled by a feedback interaction between gene-regulating small RNAs, which are inheritable, and the MOTEK genes that are required to produce and transmit these small RNAs across generations.”

“We also identified a mechanism that amplified heritable small RNAs across generations, so the response was not diluted. We found that enzymes called RdRPs are required for re-creating new small RNAs to keep the response going in subsequent generations.”

Top: GFP gene is silenced by exogenous RNA interference. Bottom: GFP gene in its active state. Image credit: study authors.

The researchers engineered flatworms to express green fluorescent protein (GFP) and then fed them on a strain of bacteria, called H115 for short, that expressed a small interfering RNA capable of silencing the flatworms’ GFP genes. As expected, the flatworms fed on those bacteria didn’t glow. But the effects didn’t stop there. Many generations later in the flatworm lineage, once the transient exposure to the interfering bacterial RNA had been bred out and the descendants’ silenced GFP genes had switched back on, the researchers exposed the descendent flatworms to a strain of H115 that only made an unrelated interfering RNA for a totally different gene. Right on cue, the lights went out.

So what’s going on here, and what does it mean for our future?

Guilty by association

During translation, while the genome is in RNA form moving between the nucleus and the ribosomes, ambient single-stranded RNAs that match the RNA sequence closely enough can bind to the RNA. But the enzymes that work with genetic material inside the cell really hate to see double-stranded RNA; the TAU researchers note in their report that because synthesis of dsRNA is associated with the presence of RNA viruses or transposons, dsRNA may constitute a “danger signal.” Just the mere presence of dsRNA seems to be enough to drum up defensive RNA interference, even if the dsRNA was targeted at a totally different gene.

The upshot is that all it takes to perpetuate an epigenetic response is exposure to a partial RNA cross-section of what was going on in the environment; even though the H115 bacteria weren’t producing a RNA that could turn off the flatworms’ GFP genes, the presence of other H115 gene products was enough to trigger the flatworms’ silencing response. This is the molecular basis of epigenetics, and the key finding of this study. DNA collects epigenetic information by exposure to its surroundings. During translation, the cell uses RdRP enzymes to parse out relevant information from genetic noise, and then passes the mature signal on to the RNAi system, which amplifies small signal inputs into systemic responses. “[This] feedback,” said Dr. Rechavi, “determines whether epigenetic memory will continue to the progeny or not, and how long each epigenetic response will last.”

RNA interference isn’t the only way epigenetic marks are made; RNAi works with histone modifications and DNA methylation to regulate transcription. Silencing genes can have a profound impact on development; indeed, epigenetic markers are the cause of Angelman’s and Prader-Willi syndromes, and have been linked to chromosomal abnormalities and cancer. The more we research, the more obvious it becomes that heredity isn’t just controlled by the linear genetic sequence. But if having a gene switched off by epigenetics can cause a disease, then maybe someday we can use epigenetics to switch it back on.