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Sins of the Father - New Research Explores How an RNA-Binding Protein Prevents Paternally-Mediated Epigenetic Sterility

August 24, 2017

 

C. elegans SUP-46, an HNRNPM family RNA-binding protein that prevents paternally-mediated epigenetic sterility

By Meghan Krizus

  Taken with a confocal microscope at our OPTIMA facility, these fluorescent images illustrate the structure of nuclei in the pachytene region of the C. elegans germline, showing a classic morphology affectionately known as a “bowl of spaghetti.”
 

Taken with a confocal microscope at our OPTIMA facility, these fluorescent images illustrate the structure of nuclei in the pachytene region of the C. elegans germline, showing a classic morphology affectionately known as a “bowl of spaghetti.”

Until the past 15 years or so, it was believed that DNA was the sole blueprint of life. Scientists and laypeople alike supposed that all phenotypes arose only from specific sequences of nucleotides in DNA. However, more recent discoveries have shown this to be untrue, and revealed the significance of epigenetic inheritance. These findings have opened up countless new avenues for the exploration of how the interplay between environment and genetics affects the organisms caught between their influences – including humans.

“We’ve known for a long time that mutations in genes lead to aberrant phenotypes,” explains Dr. Wendy Johnston. “But it’s also become clear that the environment plays a huge role…epigenetics are a way of understanding how environmental changes can be passed along.”

So what is epigenetics, and how does it affect living organisms? An epigenetic change can be most simply defined as a heritable phenotype caused by something other than a change in the actual nucleotide sequence of an organism’s DNA. Often these changes result from an environmental stressor, such as food scarcity. Because changes can be heritable, epigenetic changes can be passed down from generation to generation, meaning that an organism can suffer from the starvation experienced by its parents, grandparents, or even great-grandparents. Even though these descendants were not themselves subjected to starvation, they may carry the effects of a distant ancestor’s environment.

While epigenetic changes can confer an advantage upon an affected organism, often they can have a negative effect. Diseases ranging from diabetes to cancer have been linked to epigenetic changes, making this field a promising one for learning about and preventing disease. A new publication spearheaded by Dr. Johnston in the Dennis lab investigates just such a phenomenon. Delving into the role of SUP-46, a gene identified by Dr. Johnston and her colleagues as a novel RNA binding protein, the authors explored how dysfunction of this protein may cause paternally-mediated transgenerational sterility.

Primarily using a model organism, the nematode Caenorhabditis elegans, the team conducted a thorough study of SUP-46, studying its expression pattern using GFP, noting the conditions under which the localization of the protein changed. In collaboration with the Gingras lab, Dr. Johnston and her colleagues also discovered that SUP-46 is homologous to two human proteins, HNRNPM and MYEF2, and that these proteins bind RNA. Further, they showed that SUP-46 is crucial in protecting C. elegans against heat stress.

Perhaps most importantly, however, they found an epigenetic effect: that dysfunction of SUP-46 leads to paternally-mediated transgenerational sterility. The authors noted that over successive generations, a lack of functional SUP-46 leads to progressively higher levels of infertility, with greater numbers of hermaphrodite animals showing complete sterility as the generations passed.

Interestingly, the authors discovered that this transgenerational sterility is paternally mediated, meaning that the infertility they observed in their animals is the result of a contributions from their male ancestors. C. elegans has two naturally-occurring sexes, and the majority of animals are self-fertile hermaphrodites. These animals make both eggs and sperm and can, without mating, produce offspring. However, the low incidence of meiotic nondisjunction gives rise to males, which mate with hermaphrodites to produce progeny. Intriguingly, the sterility observed in the hermaphrodites appeared only after generations of mating with males, and did not appear when hermaphrodites gave rise to offspring that were the result of self-fertilization.

As with much of the research at LTRI, comprehensive and collaborative approaches to investigation were essential for this novel discovery. “We did both ‘big data’ science and ‘small data’ science,” explains Dr. Johnston. “A combination of using traditional tools…combined with tools that look at large data sets.” Using high-throughput techniques like RNA-Seq and BioID, as well as more traditional techniques of confocal microscopy (using equipment from our state-of-the-art OPTIMA facility), Dr. Johnston and her colleagues were able to identify what she says is a fascinating “new contributor to epigenetic inheritance.”

Dr. Johnston and co-author Aldis Krizus also stress the importance of a fundamental approach to biomedical research. “This is very much curiosity-driven research,” says Dr. Johnston. Krizus agrees, confirming that they “never would have predicted at the outset…the project going in the direction it did.” That’s what defines fundamental research!

 

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