According to epigenetics – the study of inheritable changes in gene expression not directly coded in our DNA – our life experiences may be passed on to our children and our children’s children.
Studies on survivors of traumatic events have suggested that exposure to stress may indeed have lasting effects on subsequent generations.
But how exactly are these genetic “memories” passed on? A new Tel Aviv University study pinpoints the precise mechanism that turns the inheritance of environmental influences “on” and “off.” The research, recently published 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,” Rechavi said, “but we showed that there is an active process that regulates epigenetic inheritance down through generations.”
Researchers have for years been preoccupied with how the effects of stress, trauma and other environmental exposures are passed from one generation to the next. 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 RNAs following the starvation and viral infections of their parents. These small RNAs helped prepare their offspring for similar hardships,” 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.”
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.
“This assumption ignored the possibility that this process doesn’t simply die out, but is regulated instead,” said Rechavi, who in this study treated C.elegans worms with small RNAs that target the GFP (green fluorescent protein), a “reporter gene” commonly used in experiments.
“By following heritable small RNAs 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 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 their research was conducted on worms, the researchers believe 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 doctoral student in Rechavi’s lab and first author of the paper.
“Moreover, we are planning to examine whether similar mechanisms exist in humans.”
HUMAN TEARS RESEARCH FOR BETTER CONTACT LENSES When contact lenses work really well, wearers forget they are wearing them, but they might not feel the same at the end of a long day staring at a computer screen. After too many hours of wear, the lenses and your eyes dry out, causing irritation that might outweigh the convenience of contacts.
Stanford researchers hope to alleviate this pain by both advancing the understanding of how natural tears keep our eyes comfortable and developing a machine for designing better contact lenses.
The work was inspired in part by a graduate student’s dry eyes.
“As a student, I had to stop wearing lenses due to the increased discomfort,” said Saad Bhamla, a Stanford postdoctoral scholar in bioengineering who conducted the work as a graduate student in Dr. Gerald Fuller’s chemical engineering laboratory at Stanford.
“Focusing my doctoral thesis to understand this problem was both a personal and professional goal.”
Bhamla isn’t alone. More than 30 million Americans now wear contacts, but roughly half of them switch back to glasses because of contact lens-induced symptoms such as dry eye. Bhamla and Fuller suspected that most of the discomfort arises from the breakup of the tear film, a wet coating on the surface of the eye, during a process called dewetting.
They found that the lipid layer, an oily coating on the surface of the tear film, protects the eye’s surface in two important ways – through strength and liquid retention. By mimicking the lipid layer in contact construction, millions of people could avoid ocular discomfort.
In their most recent study, Bhamla and his co-authors outline functions of the lipid layer. One is to provide mechanical strength to the tear film. Lipids in this layer have viscoelastic properties that allow them to stretch and support the watery layer beneath them.
Bhamla likens this protective lipid layer to a swimming pool cover.
You can’t run on the open water, but even a thin tarp can provide mechanical strength to support a person’s weight.
The lipid layer also prevents the tear film from evaporating away.
Eyes are roughly 35 degrees Celsius, which is usually warmer than the ambient air. Like any liquid on a hot surface, the eye is constantly heating its liquid coating and losing moisture to the air.
The key to producing comfortable contact lenses involves designing lenses that don’t destabilize the tear film. Manufacturers recognize the importance of protecting the eye’s natural tear film on a contact lens surface to minimize painful symptoms such as dry eye, but it is not an easy thing to measure.
“Some people are studying contact lenses by holding them up to a light, dipping them in water, and looking at them to see if the tear film breaks up,” Bhamla said. “We felt we could definitely do better than that.”
To solve this, Bhamla and Fuller built a device that mimics the surface of the eye. Called the Interfacial Dewetting and Drainage Optical Platform or i-DDrOP, it reproduces a tear film on the surface of a contact lens, allowing both scientists and manufacturers to systematically handle the unique array of variables.
With the ability to accurately recreate a tear film on the contact lens surface and test how quickly it breaks up, manufacturers are now armed with the tools to make a more comfortable lens that protects users from the painful side effects of wearing contacts.
Even Bhamla may trade in his glasses for a new pair of lipid-protected eyewear.