Epigenetic “remembering” is better understood than epigenetic “forgetting,” and so it is an open question whether epigenetic forgetting is, like epigenetic remembering, active—a distinct biomolecular process—or passive—a matter of dilution or decay. New research, however, suggests that epigenetic forgetting is an active process, one in which a feedback mechanism determines the duration of transgenerational epigenetic memories.

The new research comes out of Tel Aviv University, where researchers have been working with the nematode worm Caenorhabditis elegans to elucidate epigenetic mechanisms. In particular, the researchers, led by Oded Rechavi, Ph.D., have been preoccupied with how the effects of stress, trauma, and other environmental exposures are passed from one generation to the next.

In previous work, Dr. Rechavi’s team enhanced the state of knowledge of small RNA molecules, short sequences of RNA that regulate the expression of genes. The team identified a “small RNA inheritance” mechanism through which RNA molecules produced a response to the needs of specific cells and how they were regulated between generations.

“We previously showed that worms inherited small RNAs following the starvation and viral infections of their parents. These small RNAs helped prepare their offspring for similar hardships,” Dr. Rechavi explained. “We also identified a mechanism that amplified heritable small RNAs across generations, so the response was not diluted. We found that enzymes called RdRPs [RNA-dependent RNA polymerases] are required for re-creating new small RNAs to keep the response going in subsequent generations.”

Most inheritable epigenetic responses in C. elegans were found to persist for only a few generations. This created the assumption that epigenetic effects simply “petered out” over time, through a process of dilution or decay. “But this assumption,” said Dr. Rechavi, “ignored the possibility that this process doesn't simply die out but is regulated instead.”

This possibility was explored in the current study, in which C. elegans were treated with small RNAs that target the GFP (green fluorescent protein) gene, a reporter gene commonly used in experiments. “By following heritable small RNAs that regulated GFP—that 'silenced' its expression—we revealed an active, tunable inheritance mechanism that can be turned 'on' or 'off,'” declared Dr. Rechavi.

Details of the work appeared March 24 in the journal Cell, in an article entitled, “A Tunable Mechanism Determines the Duration of the Transgenerational Small RNA Inheritance in C. elegans.” The article shows that exposure to double-stranded RNA (dsRNA) activates a feedback loop whereby gene-specific RNA interference (RNAi) responses “dictate the transgenerational duration of RNAi responses mounted against unrelated genes, elicited separately in previous generations.”

Essentially, amplification of heritable exo-siRNAs occurs at the expense of endo-siRNAs. Also, a feedback between siRNAs and RNAi genes determines heritable silencing duration.

“RNA-sequencing analysis reveals that, aside from silencing of genes with complementary sequences, dsRNA-induced RNAi affects the production of heritable endogenous small RNAs, which regulate the expression of RNAi factors,” wrote the authors of the Cell paper. “Manipulating genes in this feedback pathway changes the duration of heritable silencing.”

The scientists also indicated that specific genes, which they named MOTEK (Modified Transgenerational Epigenetic Kinetics), were involved in turning on and off epigenetic transmissions.

“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. Rechavi. “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.

“The feedback determines whether epigenetic memory will continue to the progeny or not, and how long each epigenetic response will last.”

Although its research was conducted on worms, the team believes that understanding the principles that control the inheritance of epigenetic information is crucial for constructing a comprehensive theory of heredity for all organisms, humans included.

“We are now planning to study the MOTEK genes to know exactly how these genes affect the duration of epigenetic effects,” said Leah Houri-Ze'evi, a Ph.D. student in Dr. Rechavi's lab and first author of the paper. “Moreover, we are planning to examine whether similar mechanisms exist in humans.”

The current study notes that the active control of transgenerational effects could be adaptive, because ancestral responses would be detrimental if the environments of the progeny and the ancestors were different.

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