Maternal overnutrition programs hedonic and metabolic phenotypes across generations through sperm tsRNAs

Sarker, Gitalee; Sun, Wenfei; Rosenkranz, David; Pelczar, Pawel; Opitz, Lennart; Efthymiou, Vissarion; Wolfrum, Christian; Peleg‐Raibstein, Daria

doi:10.1073/pnas.1820810116

Cited by 119 publications

(111 citation statements)

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“…Yet it is increasingly clear that mammalian sperm can deliver functional RNAs to the zygote, as several studies have documented defects in preimplantation growth and development (Yuan et al, 2016) or in early embryonic gene regulation (Conine et al, , 2019Sharma et al, 2016) in embryos fertilized using sperm lacking (or supplemented with) specific small RNAs. Moreover, sperm RNAs have been implicated in mediating the effects of paternal environments on programming offspring metabolism and stress-related behaviors, as microinjection of various purified or synthetic RNAs has been shown to recapitulate a subset of paternal effect phenotypes in several studies (Chen et al, 2016;Gapp et al, 2014;Grandjean et al, 2015;Rodgers et al, 2015;Sarker et al, 2019).…”

Section: Parthenotes As a Model For Investigating Sperm Rna Functionsmentioning

confidence: 99%

Flexibility and constraint in preimplantation gene regulation in mouse

Conine

Krykbaeva

Song

et al. 2020

Preprint

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Although many features of embryonic development exhibit remarkable stability in the face of environmental perturbations, it is also clear that some aspects of early embryogenesis can be modulated by non-genetic influences during and after fertilization. Among potential perturbations experienced during reproduction, understanding the consequences of differing ex vivo fertilization methods at a molecular level is imperative for comprehending both the basic biology of early development and the potential consequences of assisted reproduction. Here, we set out to explore stable and flexible aspects of preimplantation gene expression using single-embryo RNAsequencing of mouse embryos fertilized by natural mating, in vitro fertilization, or intracytoplasmic sperm injection, as well as oocytes parthenogenetically activated to develop (parthenotes). This dataset comprises a resource of over eight hundred individual embryos, which we use for three primary analyses. First, we characterize the effects of each fertilization method on early embryonic gene regulation, most notably finding decreased expression of trophectoderm markers at later stages of preimplantation development in ICSI embryos. Second, we find massive gene misregulation in parthenotes beyond the expected defects in imprinted gene expression, and show that many of these changes can be suppressed by sperm total RNA. Finally, we make use of the single-embryo resolution of our dataset to identify both stablyexpressed genes and highly-variable genes in the early mouse embryo. Together, our data provide a detailed survey of the molecular consequences of different fertilization methods, establish parthenotes as a "tabula rasa" for understanding the role for sperm RNAs in preimplantation gene regulation, and identify subtypes of preimplantation embryos based on their expression of epivariable gene modules.

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Section: Parthenotes As a Model For Investigating Sperm Rna Functionsmentioning

confidence: 99%

Flexibility and constraint in preimplantation gene regulation in mouse

Conine

Krykbaeva

Song

et al. 2020

Preprint

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“…Both, 5' tRH-Glu-CTC and 5' tRH-Gly-GCC have been previously shown to play major roles in various cellular functions. They were amongst the sperm small RNAs that are involved in the epigenetic inheritance of paternal diet-induced metabolic disorders and addictive-like behavior in mice Sarker et al 2019;Sharma et al 2016;Zhang, Y. et al 2018). Additionally, they were found amongst a group of 5' tRHs to be upregulated in cells upon infection by the Respiratory Syncytial Virus (Wang et al 2013).…”

Section: ' Trhs Are Highly Abundant In the Hippocampus Of Primatesmentioning

confidence: 99%

“…As we found 5' tRHs like 5' tRH-Glu-CTC to be extremely abundant in small RNA libraries of primate hippocampal tissues and previous studies suggested a role in targeting genes involved in neural processes (Krishna et al 2019;Sarker et al 2019), we were interested whether the identified potential targets of 5' tRH-Glu-CTC are implicated in neuronal processes. Indeed, we found 20% of the potential shelter targets (transcripts might be stabilized), but only 5% of the potential perish targets (transcripts might be degraded) to have an assigned neuronal function.…”

Section: Non-mirna-like Targeting Rules For 5' Trhsmentioning

confidence: 99%

“…Additionally, tRFs were found to prime the reverse transcription or inhibit the promotion of retroviruses and retrotransposons (Martinez et al 2017;Ruggero et al 2014;Schorn et al 2017;Yeung et al 2009). Furthermore, tRFs are associated with several diseases such as cancer (Goodarzi et al 2015;Huang et al 2017;Lee et al 2009) and amyotrophic lateral sclerosis (Greenway et al 2006;Ivanov et al 2014) and were lately revealed to act as transgenerational transmitters that induce metabolic disorders and addictive behavior in mice Sarker et al 2019;Sharma et al 2016;Short et al 2017). While some of the described effects seem to base on similar mechanisms, tRFs from the same class were shown to trigger completely converse functions in other cases (Jehn and Rosenkranz 2019), suggesting that the regulatory potential of tRFs is more complex than observed for the well-studied major small RNA classes.…”

Section: Introductionmentioning

confidence: 99%

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5’ tRNA halves are highly expressed in the primate hippocampus and sequence-specifically regulate gene expression

Jehn

Treml

Wulsch

et al. 2019

Preprint

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Fragments of mature tRNAs have long been considered as mere degradation products without physiological function. However, recent reports show that tRNA fragments (tRFs) play prominent roles in diverse cellular processes across a wide spectrum of species. Contrasting the situation in other small RNA pathways the mechanisms behind these effects appear more diverse, more complex and are generally less well understood. In addition, surprisingly little is known about the expression profiles of tRFs across different tissues and species. Here, we provide an initial overview of tRF expression in different species and tissues, revealing very high tRF-levels particularly in the primate hippocampus.We further modulated the regulation capacity of selected tRFs in human cells by transfecting synthetic tRF mimics ("overexpression") or antisense-RNAs ("inhibition") and identified differentially expressed transcripts based on RNAseq. We then used a novel k-mer mapping approach to dissect the underlying targeting rules, demonstrating that 5' tRNA halves (5' tRHs) silence genes in a sequence-specific Jehn et al.2 manner, while the most efficient target sites align to the mid-region of the 5' tRH and are located within the CDS or 3' UTR of the target. This amends previous observations that tRFs guide Argonaut proteins to silence their targets via a miRNA-like 5' seed match and suggests a yet unknown mechanism of regulation. Finally, our data suggests that some 5' tRHs are also able to sequence-specifically stabilize mRNAs as upregulated mRNAs are also significantly enriched for 5' tRH target sites.

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“…miRs have been the most well studied small RNAs and have been proposed to regulate more than 50% of the transcriptome [23] including genes that regulate immune responses and neurodevelopment [24,25]. On the other hand, tRFs are a newly identified class of non-coding RNAs that are beginning to be linked to various biological functions, including the regulation of gene expression and epigenetics [19,[26][27][28][29][30][31][32][33][34][35][36][37][38][39][40][41][42][43][44][45]. A group of tRFs, tRNA halves, generated by cleavage at tRNA anticodon loop, can be induced by different forms of stress including viral infection and RNases in innate immune responses [46][47][48][49][50][51][52][53][54][55].…”

Section: Introductionmentioning

confidence: 99%

tRNA-derived fragments and microRNAs in the maternal-fetal interface of a mouse maternal-immune-activation autism model

Frost

Lammert

et al. 2019

Preprint

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tRNA-derived small fragments (tRFs) and tRNA halves have emerging functions in different biological pathways, such as regulating gene expression, protein translation, retrotransposon activity, transgenerational epigenetic changes and response to environmental stress. However, small RNAs like tRFs and microRNAs in the maternal-fetal interface during gestation have not been studied extensively. Here we investigated the small RNA composition of mouse placenta/decidua, which represents the interface where the mother communicates with the fetus, to determine whether there are specific differences in tRFs and microRNAs during fetal development and in response to maternal immune activation (MIA). Global tRF expression pattern, just like microRNAs, can distinguish tissue types among placenta/decidua, fetal brain and fetal liver. In particular, 5' tRNA halves from tRNA Gly , tRNA Glu , tRNA Val and tRNA Lys are abundantly expressed in the normal mouse placenta/decidua. Moreover, tRF and microRNA levels in the maternal-fetal-interface change dynamically over the course of embryonic development. To see if stress alters non-coding RNA expression at the maternal-fetal interface, we treated pregnant mice with a viral infection mimetic, which has been shown to promote autism-related phenotypes in the offspring. Acute changes in the levels of specific tRFs and microRNAs were observed 3-6 hours after MIA and are suppressed thereafter. A group of 5' tRNA halves is down-regulated by MIA, whereas a group of 18-nucleotide tRF-3a is up-regulated. In conclusion, tRFs show tissue-specificity, developmental changes and acute response to environmental stress, opening the possibility of them having a role in the fetal response to MIA.

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Maternal overnutrition programs hedonic and metabolic phenotypes across generations through sperm tsRNAs

Cited by 119 publications

References 78 publications

Flexibility and constraint in preimplantation gene regulation in mouse

Flexibility and constraint in preimplantation gene regulation in mouse

5’ tRNA halves are highly expressed in the primate hippocampus and sequence-specifically regulate gene expression

tRNA-derived fragments and microRNAs in the maternal-fetal interface of a mouse maternal-immune-activation autism model

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