Sperm RNA code programmes the metabolic health of offspring

Mammalian sperm RNA is increasingly recognized as an additional source of paternal hereditary information beyond DNA. Environmental inputs, including an unhealthy diet, mental stresses and toxin exposure, can reshape the sperm RNA signature and induce offspring phenotypes that relate to paternal environmental stressors. Our understanding of the categories of sperm RNAs (such as tRNA-derived small RNAs, microRNAs, ribosomal RNA-derived small RNAs and long non-coding RNAs) and associated RNA modifications is expanding and has begun to reveal the functional diversity and information capacity of these molecules. However, the coding mechanism endowed by sperm RNA structures and by RNA interactions with DNA and other epigenetic factors remains unknown. How sperm RNA-encoded information is decoded in early embryos to control offspring phenotypes also remains unclear. Complete deciphering of the ‘sperm RNA code’ with regard to metabolic control could move the field towards translational applications and precision medicine, and this may lead to prevention of intergenerational transmission of obesity and type 2 diabetes mellitus susceptibility.Mammalian sperm RNA carries hereditary information that regulates offspring metabolic health. This Perspectives discusses how the RNA code in sperm might be decoded in the early embryo and transformed molecular signals to influence embryonic development and offspring phenotypes.

[1]  L. Opitz,et al.  Maternal overnutrition programs hedonic and metabolic phenotypes across generations through sperm tsRNAs , 2019, Proceedings of the National Academy of Sciences.

[2]  J. B. L. Tan,et al.  Increased susceptibility of post-weaning rats on high-fat diet to metabolic syndrome , 2017, Journal of advanced research.

[3]  Wei Yan,et al.  Birth of mice after intracytoplasmic injection of single purified sperm nuclei and detection of messenger RNAs and MicroRNAs in the sperm nuclei. , 2008, Biology of reproduction.

[4]  P. Gounon,et al.  RNA-mediated non-mendelian inheritance of an epigenetic change in the mouse , 2006, Nature.

[5]  H. Yao,et al.  Effects of in Utero Exposure to Arsenic during the Second Half of Gestation on Reproductive End Points and Metabolic Parameters in Female CD-1 Mice , 2015, Environmental health perspectives.

[6]  Xudong Zhang,et al.  Dnmt2 mediates intergenerational transmission of paternally acquired metabolic disorders through sperm small non-coding RNAs , 2018, Nature Cell Biology.

[7]  Giovanni Marsico,et al.  rG4-seq reveals widespread formation of G-quadruplex structures in the human transcriptome , 2016, Nature Methods.

[8]  A. Ferguson-Smith,et al.  Identification, Characterization, and Heritability of Murine Metastable Epialleles: Implications for Non-genetic Inheritance , 2018, Cell.

[9]  Lu Wen,et al.  Single-cell multiomics sequencing and analyses of human colorectal cancer , 2018, Science.

[10]  Magdalena Zernicka-Goetz,et al.  Tracing the origin of heterogeneity and symmetry breaking in the early mammalian embryo , 2018, Nature Communications.

[11]  Tao Pan,et al.  Modifications and functional genomics of human transfer RNA , 2018, Cell Research.

[12]  Huiwen Zhu,et al.  Drug-seeking motivation level in male rats determines offspring susceptibility or resistance to cocaine-seeking behaviour , 2017, Nature Communications.

[13]  S. Bouret,et al.  Gene-environment interactions controlling energy and glucose homeostasis and the developmental origins of obesity. , 2015, Physiological reviews.

[14]  T. Hamatani.  Human spermatozoal RNAs. , 2012, Fertility and sterility.

[15]  Bin Tian,et al.  Highly sensitive sequencing reveals dynamic modifications and activities of small RNAs in mouse oocytes and early embryos , 2016, Science Advances.

[16]  Veronika A. Herzog,et al.  Small RNAs are trafficked from the epididymis to developing mammalian sperm , 2017, bioRxiv.

[17]  Francesca Tuorto,et al.  Statistically robust methylation calling for whole-transcriptome bisulfite sequencing reveals distinct methylation patterns for mouse RNAs. , 2017, Genome research.

[18]  Jason H. Moore,et al.  Missing heritability and strategies for finding the underlying causes of complex disease , 2010, Nature Reviews Genetics.

[19]  Hailing Shi,et al.  Transcriptome-wide reprogramming of N6-methyladenosine modification by the mouse microbiome , 2018, Cell Research.

[20]  J. Kurtz,et al.  Paternal knockdown of tRNA (cytosine-5-)-methyltransferase (Dnmt2) increases offspring susceptibility to infection in red flour beetles , 2018, bioRxiv.

[21]  Zhenbo Wang,et al.  Sperm-carried RNAs play critical roles in mouse embryonic development , 2017, Oncotarget.

[22]  J. McPherson,et al.  Coming of age: ten years of next-generation sequencing technologies , 2016, Nature Reviews Genetics.

[23]  Xudong Zhang,et al.  Sperm tsRNAs contribute to intergenerational inheritance of an acquired metabolic disorder , 2016, Science.

[24]  Ben Lehner,et al.  Intergenerational and transgenerational epigenetic inheritance in animals , 2019, Nature Cell Biology.

[25]  Francesca Tuorto,et al.  RNA methylation by Dnmt2 protects transfer RNAs against stress-induced cleavage. , 2010, Genes & development.

[26]  M. Meistrich,et al.  Decline in fertility of mouse sperm with abnormal chromatin during epididymal passage as revealed by ICSI. , 2005, Human reproduction.

[27]  F. Lyko.  The DNA methyltransferase family: a versatile toolkit for epigenetic regulation , 2017, Nature Reviews Genetics.

[28]  K. Godfrey,et al.  Influence of maternal obesity on the long-term health of offspring. , 2017, The lancet. Diabetes & endocrinology.

[29]  D. Moazed,et al.  Epigenetic inheritance mediated by coupling of RNAi and histone H3K9 methylation , 2018, Nature.

[30]  J. Caplan,et al.  Oviductosome-Sperm Membrane Interaction in Cargo Delivery , 2015, The Journal of Biological Chemistry.

[31]  I. Burger,et al.  Cold-induced epigenetic programming of the sperm enhances brown adipose tissue activity in the offspring , 2018, Nature Medicine.

[32]  Jenny Hansson,et al.  Pseudouridylation of tRNA-Derived Fragments Steers Translational Control in Stem Cells , 2018, Cell.

[33]  Wei Yan,et al.  SpermBase: A Database for Sperm-Borne RNA Contents , 2016, Biology of reproduction.

[34]  Germán Martínez,et al.  tRNA-derived small RNAs: New players in genome protection against retrotransposons , 2018, RNA biology.

[35]  Tong Zhou,et al.  SPORTS1.0: A Tool for Annotating and Profiling Non-coding RNAs Optimized for rRNA- and tRNA-derived Small RNAs , 2018, bioRxiv.

[36]  Wei Liu,et al.  Identification of small non-coding RNAs as sperm quality biomarkers for in vitro fertilization , 2019, Cell Discovery.

[37]  S. Krawetz,et al.  Paternal contributions: New functional insights for spermatozoal RNA , 2008, Journal of cellular biochemistry.

[38]  B. Dias,et al.  Parental olfactory experience influences behavior and neural structure in subsequent generations , 2013, Nature Neuroscience.

[39]  Martin Müller,et al.  Dynamic modulation of Dnmt2-dependent tRNA methylation by the micronutrient queuine , 2015, Nucleic acids research.

[40]  E. Miska,et al.  Transgenerational inheritance: Models and mechanisms of non–DNA sequence–based inheritance , 2016, Science.

[41]  K. Fujii,et al.  Heterogeneous Ribosomes Preferentially Translate Distinct Subpools of mRNAs Genome-wide. , 2017, Molecular cell.

[42]  Oliver J. Rando,et al.  Biogenesis and function of tRNA fragments during sperm maturation and fertilization in mammals , 2016, Science.

[43]  S. Gygi,et al.  Two RNAi Complexes, RITS and RDRC, Physically Interact and Localize to Noncoding Centromeric RNAs , 2004, Cell.

[44]  C. Thermes,et al.  Ten years of next-generation sequencing technology. , 2014, Trends in genetics : TIG.

[45]  K. Lao,et al.  Sperm-borne microRNA-34c is required for the first cleavage division in mouse , 2011, Proceedings of the National Academy of Sciences.

[46]  David I. K. Martin,et al.  Epigenetic inheritance at the agouti locus in the mouse , 1999, Nature Genetics.

[47]  Junchao Shi,et al.  tsRNAs: The Swiss Army Knife for Translational Regulation. , 2019, Trends in biochemical sciences.

[48]  Antoine H. F. M. Peters,et al.  Disruption of histone methylation in developing sperm impairs offspring health transgenerationally , 2015, Science.

[49]  Wei Yan,et al.  Alterations in sperm DNA methylation, non-coding RNA and histone retention associate with DDT-induced epigenetic transgenerational inheritance of disease , 2018, Epigenetics & Chromatin.

[50]  R. Martienssen,et al.  Tie-Break: Host and Retrotransposons Play tRNA. , 2018, Trends in cell biology.

[51]  S. Berger,et al.  Regulation of chromatin and gene expression by metabolic enzymes and metabolites , 2018, Nature Reviews Molecular Cell Biology.

[52]  Eric J Topol,et al.  High-performance medicine: the convergence of human and artificial intelligence , 2019, Nature Medicine.

[53]  R. Martienssen,et al.  Transgenerational Epigenetic Inheritance: Myths and Mechanisms , 2014, Cell.

[54]  J. Zierath,et al.  The role of diet and exercise in the transgenerational epigenetic landscape of T2DM , 2016, Nature Reviews Endocrinology.

[55]  E. Miska,et al.  Alterations in sperm long RNA contribute to the epigenetic inheritance of the effects of postnatal trauma , 2018, bioRxiv.

[56]  J. Laven,et al.  Paternal heterochromatin formation in human embryos is H3K9/HP1 directed and primed by sperm-derived histone modifications , 2014, Nature Communications.

[57]  Bing Ren,et al.  Broad histone H3K4me3 domains in mouse oocytes modulate maternal-to-zygotic transition , 2016, Nature.

[58]  F. Tang,et al.  Single-cell multi-omics sequencing of mouse early embryos and embryonic stem cells , 2017, Cell Research.

[59]  F. Tuorto,et al.  RNA cytosine methylation by Dnmt2 and NSun2 promotes tRNA stability and protein synthesis , 2012, Nature Structural &Molecular Biology.

[60]  Itamar Lev,et al.  Principles of Transgenerational Small RNA Inheritance in Caenorhabditis elegans , 2017, Current Biology.

[61]  Wei Yan,et al.  Ancestral vinclozolin exposure alters the epigenetic transgenerational inheritance of sperm small noncoding RNAs , 2016, Environmental epigenetics.

[62]  M. Patti,et al.  Paternal Exercise Improves Glucose Metabolism in Adult Offspring , 2018, Diabetes.

[63]  R. Barrès,et al.  Endurance training remodels sperm-borne small RNA expression and methylation at neurological gene hotspots , 2018, Clinical Epigenetics.

[64]  C. Workman,et al.  Obesity and Bariatric Surgery Drive Epigenetic Variation of Spermatozoa in Humans. , 2016, Cell metabolism.

[65]  Luke Isbel,et al.  Hypomethylation of ERVs in the sperm of mice haploinsufficient for the histone methyltransferase Setdb1 correlates with a paternal effect on phenotype , 2016, Scientific Reports.

[66]  C. Legrand,et al.  Mutations in Cytosine-5 tRNA Methyltransferases Impact Mobile Element Expression and Genome Stability at Specific DNA Repeats. , 2018, Cell reports.

[67]  O. Rando,et al.  Small RNAs gained during epididymal transit of sperm are essential for embryonic development in mice , 2018, bioRxiv.

[68]  M. Barna,et al.  The Discovery of Ribosome Heterogeneity and Its Implications for Gene Regulation and Organismal Life. , 2018, Molecular cell.

[69]  Yongsheng Liu,et al.  150 years of Darwin’s theory of intercellular flow of hereditary information , 2018, Nature Reviews Molecular Cell Biology.

[70]  Chen Chu,et al.  A sequence of 28S rRNA-derived small RNAs is enriched in mature sperm and various somatic tissues and possibly associates with inflammation. , 2017, Journal of molecular cell biology.

[71]  Jill P. Mesirov,et al.  RNA Duplex Map in Living Cells Reveals Higher-Order Transcriptome Structure , 2016, Cell.

[72]  R. Martienssen,et al.  LTR-Retrotransposon Control by tRNA-Derived Small RNAs , 2017, Cell.

[73]  P. Neufer,et al.  Paternal long‐term exercise programs offspring for low energy expenditure and increased risk for obesity in mice , 2016, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[74]  Junchao Shi,et al.  tsRNAs: new players in mammalian retrotransposon control , 2017, Cell Research.

[75]  Wei Yan,et al.  Sperm-borne miRNAs and endo-siRNAs are important for fertilization and preimplantation embryonic development , 2016, Development.

[76]  Y. Zhang,et al.  Allelic reprogramming of the histone modification H3K4me3 in early mammalian development , 2016, Nature.

[77]  T. Lowe,et al.  Small RNA Modifications: Integral to Function and Disease. , 2016, Trends in molecular medicine.

[78]  Wei Yan,et al.  mir-34b/c and mir-449a/b/c are required for spermatogenesis, but not for the first cleavage division in mice , 2015, Biology Open.

[79]  Paul Schimmel,et al.  The emerging complexity of the tRNA world: mammalian tRNAs beyond protein synthesis , 2017, Nature Reviews Molecular Cell Biology.

[80]  L. Farinelli,et al.  Implication of sperm RNAs in transgenerational inheritance of the effects of early trauma in mice , 2014, Nature Neuroscience.

[81]  Jie Qiao,et al.  Dynamic transcriptional symmetry-breaking in pre-implantation mammalian embryo development revealed by single-cell RNA-seq , 2015, Development.

[82]  Antoine H. F. M. Peters,et al.  In utero undernourishment perturbs the adult sperm methylome and intergenerational metabolism , 2014, Science.

[83]  Wei Li,et al.  A novel class of tRNA-derived small RNAs extremely enriched in mature mouse sperm , 2012, Cell Research.

[84]  Yoshiyuki Suzuki,et al.  An RNA-dependent RNA polymerase gene in bat genomes derived from an ancient negative-strand RNA virus , 2016, Scientific Reports.

[85]  S. Fourré,et al.  RNA-mediated paternal heredity of diet-induced obesity and metabolic disorders , 2015, Scientific Reports.

[86]  Jason D. Heaney,et al.  Transgenerational epigenetic effects of the Apobec1 cytidine deaminase deficiency on testicular germ cell tumor susceptibility and embryonic viability , 2012, Proceedings of the National Academy of Sciences.

[87]  B. Cairns,et al.  Distinctive Chromatin in Human Sperm Packages Genes for Embryo Development , 2009, Nature.

[88]  Ying Zhang,et al.  The expanding repertoire of hereditary information carriers , 2019, Development.

[89]  Schraga Schwartz,et al.  The m1A landscape on cytosolic and mitochondrial mRNA at single-base resolution , 2017, Nature.

[90]  Nicola Iovino,et al.  Functions and mechanisms of epigenetic inheritance in animals , 2018, Nature Reviews Molecular Cell Biology.

[91]  F. Tuorto,et al.  RNA–Mediated Epigenetic Heredity Requires the Cytosine Methyltransferase Dnmt2 , 2013, PLoS genetics.

[92]  Michaela Frye,et al.  RNA modifications modulate gene expression during development , 2018, Science.

[93]  Origins of lifetime health around the time of conception: causes and consequences , 2018, The Lancet.

[94]  Michael H. Schwartz,et al.  Queuosine modification protects cognate tRNAs against ribonuclease cleavage , 2018, RNA.

[95]  F. Welch,et al.  Causes and Consequences , 2017, Nature.

[96]  K. Sanders,et al.  SPORTS1.0: A Tool for Annotating and Profiling Non-coding RNAs Optimized for rRNA- and tRNA-derived Small RNAs , 2018, bioRxiv.

[97]  Antoine H. F. M. Peters,et al.  Repressive and active histone methylation mark distinct promoters in human and mouse spermatozoa , 2010, Nature Structural &Molecular Biology.

[98]  S. Krawetz,et al.  Chromatin and extracellular vesicle associated sperm RNAs , 2015, Nucleic acids research.

[99]  G. Dittmar,et al.  Queuosine‐modified tRNAs confer nutritional control of protein translation , 2018, The EMBO journal.

[100]  Wei Yan,et al.  Epigenetic inheritance of acquired traits through sperm RNAs and sperm RNA modifications , 2016, Nature Reviews Genetics.

[101]  K. Moley,et al.  Developmental and Transmittable Origins of Obesity-Associated Health Disorders. , 2017, Trends in genetics : TIG.

[102]  Bing Zhou,et al.  GRID-seq reveals the global RNA-chromatin interactome , 2017, Nature Biotechnology.

[103]  P. Itskov,et al.  Paternal Diet Defines Offspring Chromatin State and Intergenerational Obesity , 2014, Cell.

[104]  M. Patti,et al.  Epigenetic Mechanisms of Transmission of Metabolic Disease across Generations. , 2017, Cell metabolism.

[105]  G. Homanics,et al.  Heavy Chronic Intermittent Ethanol Exposure Alters Small Noncoding RNAs in Mouse Sperm and Epididymosomes , 2018, Front. Genet..

[106]  Victor O. Leshyk,et al.  The 4D nucleome project , 2017, Nature.