Faculty Spotlight: Exploring Epigenetic Inheritance via Small RNAs With Colin Conine, PhD

Editor’s Note: Meet the diverse, dedicated, and distinctive faculty who are discovering and developing pediatric life-changing solutions at Children’s Hospital of Philadelphia Research Institute, in our monthly Faculty Spotlight series. This year, we’re celebrating our internal grant recipients who are pursuing new avenues of research with this dedicated funding support. Although we cannot feature all the award recipients in this series, we congratulate their continued hard work and scientific contributions to pediatric research. In this Q&A, we meet Colin Conine, PhD, recipient of the Mentored Research Pilot Grant for Junior Faculty. Stay tuned for more from our Faculty Spotlight series throughout the year.

How long have you been at CHOP, and can you tell us about your research specialty?

I started my lab in the beginning of 2020, so I’ve been here about three and a half years.

My research focuses on how small noncoding ribonucleic acids (RNAs) regulate gene expression during development and in the germline to make gametes. More specifically, we, and others, have found that small RNAs in sperm that are regulated by the paternal environment, such as diet or stress, can transmit non-genetically or epigenetically inherited phenotypes to offspring. For example, murine models on a high fat diet sire progeny with altered metabolism compared to control sired offspring. This occurs by modulating the levels of small RNAs in the sperm to transmit the inherited phenotype.

Why did you choose to focus on that specialty?

I went to graduate school because RNA interference (RNAi) and how RNAs function as regulators of gene expression fascinated me. My first rotation was at the University of Massachusetts Chan Medical School in the lab of Craig Mello, PhD, who discovered RNAi. I worked with a gene that was thought to be involved in small RNA biogenesis in Caenorhabditis elegans, and the first thing I did was transgenically tag the gene with green fluorescent protein. The gene expressed specifically in sperm development. This finding, after many years of work, led us to the discovery that small RNAs could be packaged into sperm to transmit epigenetically inherited phenotypes to offspring. During my postdoctoral research, I demonstrated that this transmission also occurs in murine models, and I continue to work on this line of research.

What is a new avenue of research you’re able to explore as result of the Junior Faculty Award?

In collaboration with Taku Kambayashi, MD, PhD, and his lab in the Perelman School of Medicine at the University of Pennsylvania Perelman, we’ve discovered the microbiome and immune system, particularly T cells, can transmit non-genetically inherited phenotypes to their progeny, grand-progeny, and even great-grand progeny in murine models. Preliminary data supported by this award suggests that this transgenerational epigenetic inheritance occurs by the microbiome through the immune system, specifically T cells, regulating small RNAs present in sperm and eggs.

Can you tell us about a current or recent research project that you are excited about?

Currently, I am most excited by the concept that the immune system can regulate epigenetic information present in sperm to transmit non-genetically inherited phenotypes to offspring. We believe this occurs by T cells transmitting regulatory signals to epithelial cells in the epididymis — the tissue where sperm matures and is stored prior to reproduction. These signals then modulate how small RNAs are packaged into extracellular vesicles which are released into the epididymal lumen and fuse with sperm to transfer their small RNA cargo. Current projects in the lab have conclusively demonstrated that the epididymis transfers RNAs to sperm by this process. Now we need to connect the dots to T cells.

What are the long-term research questions you hope to answer?

While labs all over the world have demonstrated that the paternal environment can transmit epigenetically inherited phenotypes to progeny by regulating small RNAs in sperm, the mechanism for how this occurs is completely unknown. We want to demonstrate the functions of sperm small RNAs in regulating embryonic gene expression after fertilization and then, further, determine how this regulation is propagated throughout development to encode non-genetically inherited phenotypes. In parallel, we want to determine which RNAs in sperm have the capability of transmitting inherited phenotypes to progeny. To date, only a handful of RNAs have been studied, but there are thousands of different RNA species present in sperm that are conserved from mice to humans.