Federally funded work by UC Santa Cruz team continues broader research into how paternal environmental factors influence offspring development
By Mike Peña
March 03, 2025
The pioneering research of UC Santa Cruz’s Upasna Sharma to determine how a father’s life experiences and environment can influence the health and wellbeing of his children moves forward with the recent discovery of four genes required for male fertility and the creation of specific RNA molecules in sperm.
Sharma’s fundamental research on mice has important implications for biomedical research and influencing policies for public health. Research on mice, including Sharma’s previous work, has shown that parental environmental conditions—such as malnutrition, stress, and exposure to toxicants—can have a lasting impact on the health and well-being of their offspring. Sharma’s lab focuses on the mechanisms of how the effects of a father’s environmental conditions are transmitted to offspring—specifically, by examining changes in small non-coding RNA molecules found in sperm.
Pinpointing male fertility regulation
In their most recent study, published in the Journal of Biological Chemistry, Sharma and her team revealed a previously unknown role of four genes expressed specifically in the cells of the epididymis—a long convoluted tubule where sperm mature after they are produced in the testes. Their findings revealed that these genes play a role in male fertility and in generating small RNA molecules in mature sperm known as tRNA fragments (tRFs).
tRFs are created by cleavage of transfer RNAs (tRNAs) and are highly abundant in mature sperm. tRFs are a newly discovered class of small RNAs, and little is known about their biogenesis, according to Sharma. Various studies in the past few years, including earlier work by Sharma and others, have shown that tRFs in sperm change in response to various environmental conditions.
“This study has important implications for understanding male infertility as these genes are well conserved in humans,” said Sharma, an assistant professor of molecular, cell, and developmental biology. “These findings have opened a new area of research for our lab to understand how these four genes regulate sperm motility and fertilization capacity and how these processes are linked to small RNA processing.”
Sharma’s previous work suggested that tRFs could play a role in passing down environmentally influenced epigenetic information—information that regulates how genetic information is decoded—from one generation to the next.
As a first step to decipher how environmental information is signaled to sperm, this study’s team aimed to identify the enzymes responsible for tRNA cleavage in the epididymis. The researchers focused on four genes—Rnase9, Rnase10, Rnase11, and Rnase12—that are expressed in the epididymis. They deleted all four genes in mice and found that male mice without them were sterile.
Although their sperm could fertilize eggs in a lab dish, they could not do so naturally because they failed to pass through a key part of the female reproductive tract. These knockout sperm also had significantly lower levels of tRFs and other small RNAs—indicating that these genes play a crucial role in shaping sperm RNA composition.
“Our results suggest that sperm maturation in the epididymis is tightly linked to small RNA processing, which may influence reproductive success and even intergenerational inheritance,” Sharma said. “Understanding the underlying mechanisms of this regulation could provide new insights into how environmental factors impact sperm at the molecular level.”
Environment’s effect on sperm RNA
This study builds on Sharma’s previous research, including a pivotal 2016 paper published in Science, which demonstrated that paternal diet influences sperm RNA content. That study showed that when male mice were placed on a low-protein diet, their sperm exhibited altered levels of tRFs. One specific tRF was found to regulate early embryonic gene expression, suggesting that sperm tRFs may carry dietary information to the next generation.
Further research from other labs has corroborated these findings, showing that exposure to various environmental factors—including high-fat diets, calorie restriction, psychological stress, and chemical exposures—leads to alterations in small RNA levels in sperm of mice.
“The common observation across these studies is that small RNAs in sperm, particularly tRFs, are highly dynamic and sensitive to environmental conditions,” Sharma said. “However, how tRFs are generated in sperm was unknown.” The current study identified genes involved in tRF generation in sperm and will facilitate future studies to understand how environmental conditions alter tRF levels in sperm.
Sharma’s leading research has been deemed worthy of major support because of its aim to ultimately benefit families and public health and policy. Since joining the UC Santa Cruz faculty in 2018, she has received an NIH Director’s New Innovator Award from the National Institutes of Health in 2019 and a Searle Scholars grant in 2020. In 2021, the John Templeton Foundation awarded her a $1.18 million grant to continue her research. This latest study was supported by an NIH Director’s New Innovator Award and a Searle Scholars grant.
Other UC Santa Cruz researchers who co-authored this paper include members of the Sharma lab, including Joshua Shaffer, Alka Gupta, Andrew Holmes, and Julian Swartz, all from the Department of Molecular, Cell, and Developmental Biology, as well as Sol Katzman from the Genomics Institute. Gupta was supported by a postdoctoral fellowship from the California Institute of Regenerative Medicine (award EDUC-12759) awarded to the Institute of Biology of Stem Cells at UC Santa Cruz.
Geetika Kharkwal of Boost Neuroscience in Menlo Park, and Edgardo Linares of the University of Colorado, both former members of the Sharma lab, also contributed to the study.