Increasing lines of evidence in mammals have shown that certain acquired traits during paternal environmental exposure could be ?memorized? in sperm and transmitted to the future generations, implicating epigenetic inheritance via the sperm. Particularly, diet-induced metabolic disorders in the father are heritable in mammals, suggesting this type of epigenetic inheritance has a long-term impact in many metabolic-related human diseases. To date, the exact sperm ?epigenetic carrier? that responds to paternal dietary changes and transmits the intergenerational phenotype has remained elusive, but presumably involves DNA methylation, chromatin status or non-coding RNAs. Recently, in a high-fat diet (HFD) mouse model, we showed that highly enriched, tRNA-derived small RNAs (tsRNAs) from sperm are altered in both expression profiles and RNA modification after paternal HFD exposure. We also showed that sperm tsRNAs, along with their RNA modifications, are required for intergenerational transmission of paternally acquired metabolic disorders (Chen et.al. Science, 2016). This discovery raises the open question of how sperm tsRNAs, along with their RNA modifications, mediate the embryonic developmental programming that affects the offspring phenotype (Chen et.al. Nat Rev Genet, 2016). To understand the underlying mechanisms, we propose to (1) identify the target of sperm tsRNAs by injecting sperm tsRNAs (from HFD and control males) into zygotes, followed by comparative single-cell embryo RNA-seq of 2- to 4-cell embryos and bioinformatics analysis. (2) Because significant alterations of m5C (5-methylcytidine) in sperm tsRNAs from HFD males have been found, we will determine whether the m5C cytosine RNA methyltransferase, DNMT2, is essential for sperm tsRNAs to transmit acquired metabolic disorder to offspring, by utilizing HFD model in Dnmt2-/- and Dnmt2+/+ male mice, and injecting their sperm tsRNAs into normal zygote followed by examining the metabolic phenotype of F1 offspring. (3) Moreover, in the Dnmt2-/- versus Dnmt2+/+ HFD model, we will examine the changes of RNA expression profiles by RNA-seq, and the RNA modification profiles in sperm tsRNAs by a high-throughput approach (based on Liquid chromatography-tandem mass spectrometry, LC-MS/MS) to quantify multiple RNA modifications, which not only will detect the changes of m5C, but also discover novel RNA modification changes in the presence or absence of DNMT2. Data from the proposed study will provide insights into the mechanism by which sperm tsRNAs mediate intergenerational inheritance of acquired metabolic disorders and facilitate our understanding of the etiology of human diseases originated from diet-based transgenerational effect.

Public Health Relevance

It is known that diet-induced metabolic changes in mammals can be heritable from father to offspring. The present project will study the mechanisms by which sperm tsRNAs and their associated RNA modifications act as an ?epigenetic information carriers? that contribute to the transmission of such acquired traits. Given the pandemic obesity problem and associated metabolic disorders associated with the modern western diet, this project has the potential to revolutionize our understanding of the etiology of many types of modern human diseases originated from diet-based transgenerational effects.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD092431-02
Application #
9542349
Study Section
Cellular, Molecular and Integrative Reproduction Study Section (CMIR)
Program Officer
Moss, Stuart B
Project Start
2017-08-09
Project End
2022-06-30
Budget Start
2018-07-01
Budget End
2019-06-30
Support Year
2
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of Nevada Reno
Department
Physiology
Type
Schools of Medicine
DUNS #
146515460
City
Reno
State
NV
Country
United States
Zip Code
89557
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Chen, Qi; Shi, Junchao; Tao, Yi et al. (2018) Tracing the origin of heterogeneity and symmetry breaking in the early mammalian embryo. Nat Commun 9:1819
Zhang, Yunfang; Zhang, Xudong; Shi, Junchao et al. (2018) Dnmt2 mediates intergenerational transmission of paternally acquired metabolic disorders through sperm small non-coding RNAs. Nat Cell Biol 20:535-540
Qian, Jingjing; Zhang, Yunfang; Qu, Yongcun et al. (2018) Caffeine consumption during early pregnancy impairs oviductal embryo transport, embryonic development and uterine receptivity in mice. Biol Reprod 99:1266-1275
Shi, Junchao; Zhang, Yunfang; Zhou, Tong et al. (2018) tsRNAs: The Swiss Army Knife for Translational Regulation. Trends Biochem Sci :
Liu, Yongsheng; Chen, Qi (2018) 150 years of Darwin's theory of intercellular flow of hereditary information. Nat Rev Mol Cell Biol 19:749-750
Zhang, Yunfang; Shi, Junchao; Chen, Qi (2017) tsRNAs: new players in mammalian retrotransposon control. Cell Res 27:1307-1308