Priya Rajasethupathy, a Stanford University neuroscientist, studies how the brain records memories by looking into the molecular machinery of remembering. The most extraordinary thing she’s found is that deep, enduring memories actually change our DNA. Rajasethupathy originally wanted to be a doctor, but was influenced by her father to also be interested in computation. She graduated college in three years and volunteered with the mentally ill in India while doing neuroscience research in Bangalore. She began to wonder whether tiny molecules that are able to pause protein production, called microRNA, had anything to do with the way memory works in the brain.
She pursued this question doing a Ph.D. at Columbia and found some answers originally in the California sea slug. She and her colleagues found in 2009 that microRNA in the slug’s nerve cells helps to form memories that stay with the slug for at least 24 hours. Anda a new Tel Aviv University study pinpoints the precise mechanism that turns the inheritance of environmental influences “on” and “off.” The research, published last week in Cell and led by Dr. Oded Rechavi and his group from TAU’s Faculty of Life Sciences and Sagol School of Neuroscience, reveals the rules that dictate which epigenetic responses will be inherited, and for how long.
“Until now, it has been assumed that a passive dilution or decay governs the inheritance of epigenetic responses,” Dr. Rechavi said. “But we showed that there is an active process that regulates epigenetic inheritance down through generations.”
Passing Stress From One Generation To The Next
Researchers have been preoccupied with how the effects of stress, trauma, and other environmental exposures are passed from one generation to the next for years. Small RNA molecules — short sequences of RNA that regulate the expression of genes — are among the key factors involved in mediating this kind of inheritance. Dr. Rechavi and his team had previously 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 RNA’s following the starvation and viral infections of their parents. These small RNAs helped prepare their offspring for similar hardships,” Dr. Rechavi said. “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.”
Priya Rajasethupathy found something more interesting too. In the sea slug’s nerve cells was piRNA, a bigger molecule. When this molecule interacts with serotonin, the chemical that causes happiness and learning in the brain, piRNA allows the brain to form better memories by interacting with proteins. Rajasethupathy and her colleagues proposed that this was because the molecule alters the nerve cell’s genes. It adds chemical tags to DNA, and turns off part of the cell’s genomes, even for years. This could be a way of storing memories for years, or longer. Maybe it’s even passed down from generation to generation in the genes.
Now she’s at Stanford looking at the way mice’s brains work when storing memory.
Most inheritable epigenetic responses in C.elegans worms 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 ignored the possibility that this process doesn’t simply die out but is regulated instead,” said Dr. Rechavi, who in this study treated C.elegans worms with small RNA’s that target the GFP (green fluorescent protein), a reporter gene commonly used in experiments. “By following heritable small RNA’s that regulated GFP — that ‘silenced’ its expression — we revealed an active, tuneable inheritance mechanism that can be turned ‘on’ or ‘off.’”
The scientists discovered 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.”
A comprehensive theory of heredity?
Although their 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-Zeevi, a PhD student in Dr. Rechavi’s lab and first author of the paper. “Moreover, we are planning to examine whether similar mechanisms exist in humans.””