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RNA Velocity Reveals Altered RNA Processing Kinetics in Prenatal Hypoxic Cortex

Cassidy, Margaret M., BA1, Ahrens-Nicklas, Rebecca C., MD, PhD2, Cristancho, Ana G., MD, PhD3 1Cell and Molecular Biology Graduate Group, University of Pennsylvania, Philadelphia PA 2Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia PA 3Division of Neurology, Children's Hospital of Philadelphia, Philadelphia PA

Poster # 47

Prenatal hypoxia is a significant cause of lifelong neurodevelopmental disorders, which can lead to ne¬urological dysfunction even when hypoxia is transient and mild. Using joint single nucleus sequencing, we recently uncovered cell type-specific transcriptional and chromatin accessibility alterations in a prenatal mouse model of mild transient hypoxia. Gene ontology analysis of genes dysregulated by hypoxia in every cell type revealed differentially regulated genes related to mRNA processing. Therefore, we sought to understand if RNA processing kinetics are altered by hypoxia. Here we demonstrate alterations in cellular dynamics induced by transient hypoxia in a mouse model. RNA Velocity analysis on fetal brains exposed to prenatal hypoxia reveals alterations in RNA processing dynamics. These differences include the length of the velocity vector (i.e., the speed of differentiation) as well as latent time (i.e., trajectory inference). These data demonstrate divergent trajectories in the developing fetal brain exposed to transient hypoxia as compared to normoxic controls. Additionally, while global decreases in RNA transcription, degradation, and splicing were minimal, our analysis reveals several hypoxic-specific response genes that have altered RNA processing kinetics in response to prenatal hypoxia. These patterns help to elucidate the immediate effects of prenatal hypoxia and predict the drivers of potential long-term differences in the developing brain. Our results concerning mRNA processing differences offer the potential to identify gene and cell type-specific targets that may underlie the development of long-term developmental disabilities caused by prenatal hypoxia. As current therapeutics for prenatal hypoxia are limited and generally only reduce mortality but not morbidity, understanding cellular dynamics immediately following a hypoxic injury is crucial to the development of meaningful therapeutic interventions.

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