9 - The Role of Khdc3 in Oocyte Small RNA Expression

Poster Number: 9
Publication Number: 9.109

Matthew Smith-Raska, Weill Cornell Medicine, New York, NY, United States; Liana Senaldi, New York Presbyterian Hospital - Weill Cornell Medicine, New York, NY, United States; Nora Hassan, Weill Cornell Medicine, Staten Island, NY, United States

Background:
It is becoming increasingly apparent that our ancestor’s experiences such as diet or stress can influence the risk of disease in unexposed descendants, often across multiple generations.  This phenomenon is broadly referred to as epigenetic inheritance, which describes the process by which an exposure such as diet or stress can change the non-DNA factors in sperm and oocytes, which are inherited at fertilization and have a significant effect on development and risk of disease in descendants.  Small RNAs such as piwiRNA and tRNA fragments are being increasingly recognized as critical components of this process, but the cellular mechanism by which an exposure affects the small RNA profile of germ cells remains undescribed.  This process of epigenetic inheritance can potentially provide a mechanistic explanation for the many strongly inherited pediatric diseases that genomics-based approaches have largely been unable to explain.

Objective: We study a mammalian gene that we hypothesize is important for small RNA accumulation in germ cells in response to environmental exposures.  Our objective is to examine whether this gene is critical for the small RNA profile in germ cells in response to in utero exposure to dexamethasone.

Design/Methods: We generated a knockout mouse and examined the small RNA machinery in the oocytes of this mouse, as well as how the small RNAs change in response to in utero exposure to dexamethasone.

Results:
Using a knockout mouse, we demonstrate that the developing germ cells have abnormal expression of small RNA-processing genes, and that knockout mature oocytes have an abnormal profile of small RNAs such as microRNAs, piwiRNAs, and tRNA fragments.  We further demonstrate that the knockout mouse fails to induce oocyte small RNAs in response to in utero exposure to dexamethasone, suggesting that this gene is an important regulator of the small RNA response to exposures, with implications for inheritance of diseases in response to ancestral exposures across multiple generations.
Conclusion(s): Our data suggest that this gene is an important regulator of small RNA changes to oocytes in response to environmental exposures, which provides original mechanistic insight into how one's experiences can affect the risk of disease in their descendants.