Sperm RNA code programmes the metabolic health of offspring

Zhang, Yunfang; Shi, Junchao; Rassoulzadegan, Minoo; Tuorto, Francesca; Chen, Qi

doi:10.1038/s41574-019-0226-2

Cited by 186 publications

(144 citation statements)

References 105 publications

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“…BMI is commonly used as a measure of obesity which in mice, is associated with altered small noncoding sperm RNA, DNA methylation and DNA fragmentation. Such effects may be epigenetically heritable [14,21,23,[25][26][27]33]. Human studies have identified a series of associations of paternal BMI to birth outcome and offspring phenotype [18][19][20].…”

Section: Discussionmentioning

confidence: 99%

“…Highlighting the importance of the paternal contribution to a child's health, these have been extended to include paternal obesity associations with birth success, birth weight and a child's phenotypic traits such as metabolic health and over-all longevity [14,[16][17][18][19][20][21]. Animal models have identified alterations in sperm DNA methylation and RNAs in response to high fat and protein diets [21][22][23][24], some of which are inherited by the next generation resulting in metabolic disorders [23,[25][26][27]. Studies by Ortega et al [28] identified a number of circulating miRNAs altered in response to obesity, while Donkin et al [29] identified altered DNA methylation and small RNAs in sperm when lean and obese men were compared.…”

Section: Introductionmentioning

confidence: 99%

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Human chromatin remodeler cofactor, RNA interactor, eraser and writer sperm RNAs responding to obesity

et al. 2019

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In the United States almost 33% of adults are considered obese (BMI > 30 kg/m 2). Both animal models and to a lesser extent human studies, have associated BMI, a measure of obesity, with alterations in sperm DNA methylation and RNAs. Sperm RNAs from the Assessment of Multiple Gestations from Ovarian Stimulation trial, were isolated and sequenced. A Generalized Linear Model identified 487 BMI associated human sperm RNA elements (short exon-sized sequences). They partitioned into four patterns; a continual increase with BMI, increase once obese (BMI>30 kg/m 2); a steady decrease with BMI; and decrease once overweight (BMI 25-30 kg/ m 2). Gene Ontology revealed a unique relationship between BMI and transcripts associated with chromosome organization, adipogenesis, cellular stress and obesity-related inflammation. Coregulatory networks linked by Chromatin remodeler cofactors, RNA interactors, Erasers and Writers (CREWs) were uncovered to reveal a hierarchical epigenetic response pathway.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Human chromatin remodeler cofactor, RNA interactor, eraser and writer sperm RNAs responding to obesity

et al. 2019

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“…This is robustly supported by studies in mice [24,26,28], but due to ethical constraint, such studies are difficult to perform on humans. Even though the recent study on embryo quality by Hua and colleagues [34] supports this idea, conclusive evidence that the human egg cell is responding to changes in the pool of sperm sncRNA, or what has been termed the sncRNA code [63], is missing. We have, however, shown that human sperm has the plasticity to reconfigure the sperm sncRNA code in response to rapid environmental changes, which in other species has served as a message to the next generation.…”

Section: Is There a Role For Tsrna In Metabolic Intergenerational Effmentioning

confidence: 99%

Human sperm displays rapid responses to diet

et al. 2019

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The global rise in obesity and steady decline in sperm quality are two alarming trends that have emerged during recent decades. In parallel, evidence from model organisms shows that paternal diet can affect offspring metabolic health in a process involving sperm tRNAderived small RNA (tsRNA). Here, we report that human sperm are acutely sensitive to nutrient flux, both in terms of sperm motility and changes in sperm tsRNA. Over the course of a 2-week diet intervention, in which we first introduced a healthy diet followed by a diet rich in sugar, sperm motility increased and stabilized at high levels. Small RNA-seq on repeatedly sampled sperm from the same individuals revealed that tsRNAs were up-regulated by eating a high-sugar diet for just 1 week. Unsupervised clustering identified two independent pathways for the biogenesis of these tsRNAs: one involving a novel class of fragments with specific cleavage in the T-loop of mature nuclear tRNAs and the other exclusively involving mitochondrial tsRNAs. Mitochondrial involvement was further supported by a similar up-regulation of mitochondrial rRNA-derived small RNA (rsRNA). Notably, the changes in sugarsensitive tsRNA were positively associated with simultaneous changes in sperm motility and negatively associated with obesity in an independent clinical cohort. This rapid response to a dietary intervention on tsRNA in human sperm is attuned with the paternal intergenerational metabolic responses found in model organisms. More importantly, our findings suggest shared diet-sensitive mechanisms between sperm motility and the biogenesis of tsRNA, which provide novel insights about the interplay between nutrition and male reproductive health.

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“…Interestingly, in sperm, RNAs can be localized in main compartments: (i) extra-nuclear compartment that includes the plasma membrane, the acrosome and associated membranes; (ii) the intra-nuclear compartment which includes the nucleus, the nuclear envelope and the perinuclear theca; (iii) mitochondria. Most mRNAs and rsRNAs are attached to the sperm outer membrane [55] and a possible exocytosis of these molecules in extracellular vesicles has been hypothesized [56]. On the other hand, tsRNAs and miRNAs appear imbedded in the nuclear envelop; it cannot be ruled out that a population of RNAs may directly contact DNA forming highly structured RNA-DNA complexes [57].…”

Section: Sperm Rna Codementioning

confidence: 99%

Histone Post-Translational Modifications and CircRNAs in Mouse and Human Spermatozoa: Potential Epigenetic Marks to Assess Human Sperm Quality

Chioccarelli

Pierantoni

Manfrevola

et al. 2020

JCM

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Spermatozoa (SPZ) are motile cells, characterized by a cargo of epigenetic information including histone post-translational modifications (histone PTMs) and non-coding RNAs. Specific histone PTMs are present in developing germ cells, with a key role in spermatogenic events such as self-renewal and commitment of spermatogonia (SPG), meiotic recombination, nuclear condensation in spermatids (SPT). Nuclear condensation is related to chromatin remodeling events and requires a massive histone-to-protamine exchange. After this event a small percentage of chromatin is condensed by histones and SPZ contain nucleoprotamines and a small fraction of nucleohistone chromatin carrying a landascape of histone PTMs. Circular RNAs (circRNAs), a new class of non-coding RNAs, characterized by a nonlinear back-spliced junction, able to play as microRNA (miRNA) sponges, protein scaffolds and translation templates, have been recently characterized in both human and mouse SPZ. Since their abundance in eukaryote tissues, it is challenging to deepen their biological function, especially in the field of reproduction. Here we review the critical role of histone PTMs in male germ cells and the profile of circRNAs in mouse and human SPZ. Furthermore, we discuss their suggested role as novel epigenetic biomarkers to assess sperm quality and improve artificial insemination procedure.

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Sperm RNA code programmes the metabolic health of offspring

Cited by 186 publications

References 105 publications

Human chromatin remodeler cofactor, RNA interactor, eraser and writer sperm RNAs responding to obesity

Human chromatin remodeler cofactor, RNA interactor, eraser and writer sperm RNAs responding to obesity

Human sperm displays rapid responses to diet

Histone Post-Translational Modifications and CircRNAs in Mouse and Human Spermatozoa: Potential Epigenetic Marks to Assess Human Sperm Quality

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