Dnmt2 mediates intergenerational transmission of paternally acquired metabolic disorders through sperm small non-coding RNAs

Zhang, Yunfang; Zhang, Xudong; Shi, Junchao; Tuorto, Francesca; Li, Xin; Liu, Yusheng; Liebers, Reinhard; Zhang, Liwen; Qu, Yongcun; Qian, Jingjing; Pahima, Maya; Liu, Ying; Yan, Menghong; Cao, Zhen-Dong; Lei, Xiaohua; Cao, Yuqi; Peng, Hongying; Liu, Shichao; Wang, Yue; Zheng, Huili; Woolsey, Rebekah; Quilici, David R.; Zhai, Qiwei; Li, Lei; Zhou, Tong; Yan, Wei; Lyko, Frank; Zhang, Ying; Zhou, Qi; Duan, Enkui; Chen, Qi

doi:10.1038/s41556-018-0087-2

Cited by 327 publications

(415 citation statements)

References 42 publications

(74 reference statements)

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“…Followup work showed that DNMT2 was responsible for these modifications. In contrast to wild-type animals, DNMT2 knockout mice failed to demonstrate a relative enrichment of m 5 C or m 2 G in the tRNA fragments after HFD [139]. The DNMT2 knockout mice fed a HFD did still produce tRNA fragments; in fact, they produced higher levels of tRNA fragments in agreement with previously reported data on DNMT2-mediated regulation of tRNA cleavage [103].…”

Section: Constitutive Trna Fragmentssupporting

confidence: 89%

The role of RNA modifications in the regulation of tRNA cleavage

2018

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Transfer RNA (tRNA) have been harbingers of many paradigms in RNA biology. They are among the first recognized noncoding RNA (ncRNA) playing fundamental roles in RNA metabolism. Although mainly recognized for their role in decoding mRNA and delivering amino acids to the growing polypeptide chain, tRNA also serve as an abundant source of small ncRNA named tRNA fragments. The functional significance of these fragments is only beginning to be uncovered. Early on, tRNA were recognized as heavily post-transcriptionally modified, which aids in proper folding and modulates the tRNA:mRNA anticodon-codon interactions. Emerging data suggest that these modifications play critical roles in the generation and activity of tRNA fragments. Modifications can both protect tRNA from cleavage or promote their cleavage. Modifications to individual fragments may be required for their activity. Recent work has shown that some modifications are critical for stem cell development and that failure to deposit certain modifications has profound effects on disease. This review will discuss how tRNA modifications regulate the generation and activity of tRNA fragments.

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Section: Constitutive Trna Fragmentssupporting

confidence: 89%

The role of RNA modifications in the regulation of tRNA cleavage

2018

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“…In rodents, the triggering by high-fat diet of the metabolic disorder underlying obesity and diabetes is transmitted to offspring even if the latter eat healthy food. This transmission occurs through the transmission of small non-coding RNAs (sncRNAs) carried by sperm cells (Chen et al, 2016a;Zhang et al, 2018;review in Chen et al, 2016b). These RNAs are likely acquired by sperm cells during sperm transit in the epididymis (Sharma et al, 2016) in an intriguing form of soma to germen communication.…”

Section: Inheritance Of Acquired Disordersmentioning

confidence: 99%

Epigenetically facilitated mutational assimilation: epigenetics as a hub within the inclusive evolutionary synthesis

et al. 2018

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After decades of debate about the existence of non‐genetic inheritance, the focus is now slowly shifting towards dissecting its underlying mechanisms. Here, we propose a new mechanism that, by integrating non‐genetic and genetic inheritance, may help build the long‐sought inclusive vision of evolution. After briefly reviewing the wealth of evidence documenting the existence and ubiquity of non‐genetic inheritance in a table, we review the categories of mechanisms of parent–offspring resemblance that underlie inheritance. We then review several lines of argument for the existence of interactions between non‐genetic and genetic components of inheritance, leading to a discussion of the contrasting timescales of action of non‐genetic and genetic inheritance. This raises the question of how the fidelity of the inheritance system can match the rate of environmental variation. This question is central to understanding the role of different inheritance systems in evolution. We then review and interpret evidence indicating the existence of shifts from inheritance systems with low to higher transmission fidelity. Based on results from different research fields we propose a conceptual hypothesis linking genetic and non‐genetic inheritance systems. According to this hypothesis, over the course of generations, shifts among information systems allow gradual matching between the rate of environmental change and the inheritance fidelity of the corresponding response. A striking conclusion from our review is that documented shifts between types of inherited non‐genetic information converge towards epigenetics (i.e. inclusively heritable molecular variation in gene expression without change in DNA sequence). We then interpret the well‐documented mutagenicity of epigenetic marks as potentially generating a final shift from epigenetic to genetic encoding. This sequence of shifts suggests the existence of a relay in inheritance systems from relatively labile ones to gradually more persistent modes of inheritance, a relay that could constitute a new mechanistic basis for the long‐proposed, but still poorly documented, hypothesis of genetic assimilation. A profound difference between the genocentric and the inclusive vision of heredity revealed by the genetic assimilation relay proposed here lies in the fact that a given form of inheritance can affect the rate of change of other inheritance systems. To explore the consequences of such inter‐connection among inheritance systems, we briefly review published theoretical models to build a model of genetic assimilation focusing on the shift in the engraving of environmentally induced phenotypic variation into the DNA sequence. According to this hypothesis, when environmental change remains stable over a sufficient number of generations, the relay among inheritance systems has the potential to generate a form of genetic assimilation. In this hypothesis, epigenetics appears as a hub by which non‐genetically inherited environmentally induced variation in traits can be...

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“…These epididymis-synthesized sncRNAs, including miRNAs, tsRNAs, and perhaps the rsRNA-28S, are therefore delivered to the zygote as vital epigenetic information and involved in the regulation of certain early embryonic events and even have profound consequence to the development of the offspring (Chen et al, 2016a;Sharma et al, 2016;Zhang et al, 2018). These epididymis-synthesized sncRNAs, including miRNAs, tsRNAs, and perhaps the rsRNA-28S, are therefore delivered to the zygote as vital epigenetic information and involved in the regulation of certain early embryonic events and even have profound consequence to the development of the offspring (Chen et al, 2016a;Sharma et al, 2016;Zhang et al, 2018).…”

Section: Progress Over the Past Decadementioning

confidence: 99%

“…Some other sncRNA containing epididymosomes transfer their cargos to the passing spermatozoa. These epididymis-synthesized sncRNAs, including miRNAs, tsRNAs, and perhaps the rsRNA-28S, are therefore delivered to the zygote as vital epigenetic information and involved in the regulation of certain early embryonic events and even have profound consequence to the development of the offspring (Chen et al, 2016a;Sharma et al, 2016;Zhang et al, 2018). The biological significance for the spermatozoa to obtain these sncRNAs during epididymal transit was further emphasized by the study showing that embryos generated using mouse caput epididymal spermatozoa tended to fail soon after implantation, and the microinjection of purified cauda-specific sncRNAs into these embryos can rescue this lethality phenotype .…”

Section: Extensive Functions Of the Epididymal Sncrnas: From In Situ mentioning

confidence: 99%

Epididymal small non‐coding RNA studies: progress over the past decade

Chu

Zhang

et al. 2019

Andrology

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Background: Small non-coding RNAs (sncRNAs) accomplish a huge variety of biological functions. Over the past decade, we have witnessed the substantial progress in the epididymal sncRNA studies. In the Epididymis 7, we had the true privilege of having a whole session to share our findings and exchange ideas on the epididymal sncRNA studies. Objectives: This mini-review attempts to provide an overview of what is known about the sncRNAs in the mammalian epididymis and discuss the future directions in this field. Methods: We surveyed literature regarding the sncRNA studies in the mammalian epididymis, and integrated some of our unpublished findings as well. We focus on the progress in methodology and the advances in our understanding of the expression and functions of epididymal sncRNAs. Results and Discussion: The applications of high-throughput approaches have made great contributions in the discovery of new sncRNA species and profiling their dynamics in the epithelial cells, the passing spermatozoa, and the luminal environment. The diverse classes of epididymal sncRNAs exert important biological functions from the in situ regulation of epididymal gene expression to the epigenetic inheritance in the offspring. Conclusion: Although still in its infancy, we believe that the research on epididymal sncRNAs will not only lead to a better understanding of their physiological and pathological functions, but also contribute to the whole landscape of the RNA field.

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Dnmt2 mediates intergenerational transmission of paternally acquired metabolic disorders through sperm small non-coding RNAs

Cited by 327 publications

References 42 publications

The role of RNA modifications in the regulation of tRNA cleavage

The role of RNA modifications in the regulation of tRNA cleavage

Epigenetically facilitated mutational assimilation: epigenetics as a hub within the inclusive evolutionary synthesis

Epididymal small non‐coding RNA studies: progress over the past decade

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