Research Finds RNAs in Sperm Influence Offspring Phenotype

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Neonatology Update

During fertilization, a sperm and egg cells unite to combine genetic information provided by both parents. For years, researchers have assumed fertilizing the egg was the primary role of sperm. But sperm do more than transmit paternal genes: They deliver a complex payload of RNA molecules that can modulate inherited characteristics of offspring.

In the last 10 to 15 years, researchers have learned that the paternal environment—including diet and stress—causes changes in small RNAs carried by the sperm and impacts offspring traits like metabolism and behaviors.

This forms the foundation of research for Colin Conine, PhD, an investigator with Children’s Hospital of Philadelphia’s Division of Neonatology. For his research in this area, Dr. Conine was named a 2021 Pew Scholar in the Biomedical Sciences. With four years of funding from Pew, Dr. Conine will elucidate the mechanisms behind this form of epigenetic inheritance in more detail than ever before.

Although historically RNAs have been thought of as intermediaries that help translate information from the DNA in our genes into functional proteins in our bodies, it is now also understood that RNA can play a regulatory role, helping to turn genes on or off. This often occurs via small, noncoding regulatory RNAs. When it comes to sperm, prior studies have shown that the paternal environment can regulate these small regulatory RNAs in sperm, with changes in diet leading to changes in transfer RNA (tRNA) fragments, whereas stress influences microRNAs.

However, there are millions of RNAs in sperm, many of which have not been identified and characterized. That’s where Dr. Conine’s research comes in. Dr. Conine’s research has already demonstrated that sperm RNAs can regulate embryonic gene expression after fertilization and that this regulation is important for embryo implantation and development.

With the help of the Pew Award, researchers in his lab are using state-of-the-art techniques in reproductive biology, molecular biology, genomics, biochemistry, and genetics to characterize all RNAs in sperm across multiple species. Once he and his team provide a comprehensive overview of all the RNAs in sperm, they plan to test what impact those RNAs have on the next generation, learning what various RNAs regulate and how they impact offspring.

This work will provide insights into the inheritance and predisposition of disease and potentially lead to novel treatments for male fertility and developmental disorders.

Research in Focus

Dr. Conine’s lab is particularly interested in how RNAs present in sperm are capable of transmitting non-genetic information to their progeny, influencing offspring phenotype. This includes:

  • How small RNAs regulate gene expression in the male germline to support spermatogenesis and fertility
  • How small RNAs are packaged into mature sperm
  • How RNAs transmitted during fertilization are able to regulate early embryonic gene expression and development
  • How this regulation can alter developmental programs to produce a non-genetically inherited phenotype

“The fact that this happens specifically from the male side is particularly interesting,” says Conine. “For years, it’s been thought that sperm only contribute the genome. But this work— it’s background and our current research—makes people really reconsider how we think about fertilization and the role of sperm in early development.”