Physiologic variation in sperm miRNAs tune embryonic gene regulatory programs and developmental outcomes
Grace S Lee1,2, James Garifallou3, Samantha L Higgins4
1Pharmacology Graduate Group, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
Biorxiv : the Preprint Server for Biology
|March 23, 2026
Summary
Sperm microRNAs (miRNAs) can program offspring development. Even small changes in sperm miRNA levels quantitatively alter embryonic gene expression and cause developmental phenotypes, demonstrating a novel epigenetic inheritance mechanism.
Area of Science:
- Epigenetics
- Developmental Biology
- Molecular Biology
Background:
- Sperm small RNAs, including microRNAs (miRNAs), are implicated in transgenerational epigenetic inheritance.
- Mechanisms by which sperm miRNAs influence embryonic development despite egg dilution are unclear.
Purpose of the Study:
- To investigate how variations in sperm miRNA abundance quantitatively affect embryonic gene expression and developmental outcomes.
- To elucidate the mechanisms of early miRNA-mediated gene regulation in embryos.
Main Methods:
- Utilized parthenogenetic and fertilized embryos to study miRNA effects.
- Developed AGO2-REMORA, an RNA adenosine base editor fused to Argonaute2, for mapping miRNA-mRNA interactions.
- Quantified dose-dependent responses to specific miRNAs (miR-200c-3p, miR-465c-3p).
Main Results:
- As few as 200 molecules of specific sperm miRNAs can induce dose-dependent gene expression changes.
- Parthenogenetic embryos confirmed early miRNA-driven gene expression.
- AGO2-REMORA revealed direct miRNA targeting and secondary transcriptional effects.
- Elevated miR-200c-3p induced craniofacial phenotypes, mimicking fetal alcohol syndrome features.
Conclusions:
- Physiologically relevant variations in sperm miRNA content quantitatively program embryonic development.
- Early miRNA-mRNA interactions initiate regulatory cascades with lasting effects on offspring phenotype.
- This study provides a framework for understanding sperm miRNA-mediated developmental programming.
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