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Principal Investigator: Qi Chen
Organization: UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH
Fiscal Year: 2024
Award: $703,373
Funding agency: Eunice Kennedy Shriver National Institute of Child Health and Human Development
Project summary:
Increasing lines of evidence in mammals have shown that certain acquired traits during paternal environmental
exposure (e.g., unhealthy diet) can be “memorized” in sperm and transmitted to the future generations without
altering the DNA sequence. Our research seeks to unravel the epigenetic mechanisms by which paternal
environmental factors, like diet, are encoded in sperm RNA and influence offspring health. Building on our
discovery of tRNA-derived small RNAs (tsRNAs) and rRNA-derived small RNAs (rsRNAs) in sperm and their
role in intergenerational inheritance, we have raised the concept of 'sperm RNA code'—an RNA
expression/modification signature—that is sensitive to paternal experiences such as diet and stress. However,
the mechanisms by which sperm tsRNAs/rsRNAs and their modifications impact offspring by penetrating the
embryo development process remain largely unknown and await to be addressed. This renewal of our NIH R01
project aims to advance the study of epigenetic inheritance via sperm RNAs, which will extend from our
innovative tools developed from the last funding period, including PANDORA-seq, which uncovers modified
tsRNA/rsRNA that are previously undetectable; and MLC-seq, a novel mass spectrometry-based method to map
multiple RNA modifications of tsRNAs/rsRNAs. We’ll use these new tools to uncover the alterations of
tsRNAs/rsRNAs and their RNA modification under high-fat diet (HFD), and how they regulate offspring
phenotype via early embryonic events such as lineage differentiation. Our preliminary data reveal that tsRNAs
and rsRNAs are uniquely expressed in sperm heads, and that some of them are regulators of cell lineage
differentiation in mouse embryonic stem cells, leading to the hypothesis that they can skew the embryonic lineage
balance between the inner-cell mass (ICM) and trophectoderm (TE), thus a mechanism for influencing balanced
fetus-placenta development. We will systematically explore this potential mechanism by 1) leverage PANDORA-
seq and MLC-seq to identify the modified sperm tsRNAs/rsRNAs responsive to HFD and to examine their roles
by zygotic RNA injection regarding regulations on embryonic cell fate decisions and subsequent fetus:placenta
development; 2) quantify the relationship between dysregulated fetus-placenta weight ratio during mid- and late-
pregnancy to metabolic phenotypes in offspring in a sex-specific manner. 3) Investigate the molecular interplay
of tsRNAs/rsRNAs with nuclear ribonucleoproteins, providing insights into how these interactions may regulate
ribosomal function and translational specificity and thus, embryonic cell lineage outcomes. Collectively, this
research strives to dissect the complex cellular mechanisms underpinning paternal environmental exposure-
induced epigenetic inheritance. It aims to establish deeper insight in understanding the cellar and developmental
origin of sperm RNA-induced epigenetic inheritance upon paternal environmental exposure.
Terms: <21+ years old><Address><Adult><Adult Children><Adult Daughters><Adult Human><Adult Offspring><Adult Sons><Aging><Biogenesis><Biological Function><Biological Process><Cell Body><Cell Lineage><Cell Nucleus><Cells><Cells Placenta-Tissue><Code><Coding System><Coin><Complex><DNA Sequence><Data><Detection><Development><Diet><Disease><Disorder><EC 2.1.1><Embryo><Embryo Development><Embryoblast><Embryogenesis><Embryonic><Embryonic Development><Environmental Exposure><Environmental Factor><Environmental Risk Factor><Epigenetic><Epigenetic Change><Epigenetic Mechanism><Epigenetic Process><Equilibrium><Event><Exhibits><Fathers><Fetus><Functional RNA><Funding><Future Generations><Gene Transcription><Genetic Transcription><Gestation><Health><High Fat Diet><Inflammation><Injections><Inner Cell Mass><Intervention><Intervention Strategies><Investigators><Late pregnancy><Mammalia><Mammals><Maps><Mass Photometry/Spectrum Analysis><Mass Spectrometry><Mass Spectroscopy><Mass Spectrum><Mass Spectrum Analyses><Mass Spectrum Analysis><Measures><Mediating><Memory><Messenger RNA><Metabolic><Metabolic Diseases><Metabolic Disorder><Methods><Methyltransferase><Mice><Mice Mammals><Modeling><Modification><Molecular><Mouse Embryonic Progenitor><Mouse Embryonic Stem Cells><Murine><Mus><NIH><National Institutes of Health><Non-Coding><Non-Coding RNA><Non-Polyadenylated RNA><Non-translated RNA><Noncoding RNA><Nontranslated RNA><Normal Placentoma><Nuclear><Nucleus><Onset of illness><Origin of Life><Outcome><Penetration><Phenotype><Placenta><Placenta Embryonic Tissue><Placental Development><Placentation><Placentome><Pregnancy><Process><RNA><RNA Binding><RNA Expression><RNA Gene Products><RNA Seq><RNA bound><RNA sequencing><RNAseq><Regulation><Research><Research Personnel><Researchers><Ribonucleic Acid><Ribonucleoproteins><Ribosomal Biogenesis Pathway><Ribosomal RNA><Ribosomes><Role><Shapes><Site><Small RNA><Specificity><Sperm><Sperm Head><Spermatozoa><Stress><Thesaurismosis><Transcription><Transfer RNA><Transmission><Triplet Codon-Amino Acid Adaptor><Tumor Suppressor Arf Inhibits Ribosomal Biogenesis><Unhealthy Diet><United States National Institutes of Health><Untranslated RNA><Weight><adulthood><balance><balance function><developmental><dietary><diets><disease onset><disorder onset><embryo cell><environmental risk><epigenetically><experience><innovate><innovation><innovative><insight><intergenerational><interventional strategy><mRNA><metabolic phenotype><metabolism disorder><metabotype><methylase><noncoding><novel><offspring><poor diet><pre-implantation><preimplantation><prevent><preventing><progenitor cell model><progenitor model><rRNA><risk mitigation><sex><social role><sperm cell><spermatozoon head><stem and progenitor cell model><stem cell based model><stem cell derived model><stem cell model><tRNA><tool><trait><transcriptome sequencing><transcriptomic sequencing><transfer Ribonucleic acids><transmethylase><transmission process><weights><zoosperm>