TY - JOUR
T1 - Dnmt2 mediates intergenerational transmission of paternally acquired metabolic disorders through sperm small non-coding RNAs
AU - Zhang, Yunfang
AU - Zhang, Xudong
AU - Shi, Junchao
AU - Tuorto, Francesca
AU - Li, Xin
AU - Liu, Yusheng
AU - Liebers, Reinhard
AU - Zhang, Liwen
AU - Qu, Yongcun
AU - Qian, Jingjing
AU - Pahima, Maya
AU - Liu, Ying
AU - Yan, Menghong
AU - Cao, Zhonghong
AU - Lei, Xiaohua
AU - Cao, Yujing
AU - Peng, Hongying
AU - Liu, Shichao
AU - Wang, Yue
AU - Zheng, Huili
AU - Woolsey, Rebekah
AU - Quilici, David
AU - Zhai, Qiwei
AU - Li, Lei
AU - Zhou, Tong
AU - Yan, Wei
AU - Lyko, Frank
AU - Zhang, Ying
AU - Zhou, Qi
AU - Duan, Enkui
AU - Chen, Qi
N1 - Funding Information:
This research was supported by the Ministry of Science and Technology of China (2016YFA0500903 to E.D., 2015CB943000 to Ying Z., 2012CBA01300 to Q.Zhou, 2017YFC1001401 to E.D.), the Strategic Priority Research Program of the Chinese Academy of Sciences (XDA01020101 to Q.Zhou, XDB19000000 to Q.Zhai and XDA12030204 to M.Y.), the National Natural Science Foundation of China (31671568 and 81490742 to E.D., 31671201 to Ying Z., 31630037 to Q.Zhai, 31701308 to Z.C., 31670830 and 81472181 to M.Y), Youth Innovation Promotion Association, CAS (no. 2016081 to Ying Z.), NIH grant (R01HD092431 and P30GM110767-03 to Q.C.; HD085506 and P30GM110767 to W.Y.), Templeton Foundation (PID: 50183 to W.Y.), Nevada INBRE (GM103440 to D.Q., M.P. and Q.C.), Baden-Württemberg Stiftung (Forschungsprogramm ‘nicht-kodierende RNAs’) and Deutsche Forschungsgemeinschaft (Priority Programme 1784) to F.L. F.T. is supported by the Institute of Genetics and Biophysics A. Buzzati-Traverso, C.N.R., Italy.
Publisher Copyright:
© 2018 The Author(s).
PY - 2018/5/1
Y1 - 2018/5/1
N2 - The discovery of RNAs (for example, messenger RNAs, non-coding RNAs) in sperm has opened the possibility that sperm may function by delivering additional paternal information aside from solely providing the DNA 1 . Increasing evidence now suggests that sperm small non-coding RNAs (sncRNAs) can mediate intergenerational transmission of paternally acquired phenotypes, including mental stress 2,3 and metabolic disorders 4-6 . How sperm sncRNAs encode paternal information remains unclear, but the mechanism may involve RNA modifications. Here we show that deletion of a mouse tRNA methyltransferase, DNMT2, abolished sperm sncRNA-mediated transmission of high-fat-diet-induced metabolic disorders to offspring. Dnmt2 deletion prevented the elevation of RNA modifications (m 5 C, m 2 G) in sperm 30-40 nt RNA fractions that are induced by a high-fat diet. Also, Dnmt2 deletion altered the sperm small RNA expression profile, including levels of tRNA-derived small RNAs and rRNA-derived small RNAs, which might be essential in composing a sperm RNA 'coding signature' that is needed for paternal epigenetic memory. Finally, we show that Dnmt2-mediated m 5 C contributes to the secondary structure and biological properties of sncRNAs, implicating sperm RNA modifications as an additional layer of paternal hereditary information.
AB - The discovery of RNAs (for example, messenger RNAs, non-coding RNAs) in sperm has opened the possibility that sperm may function by delivering additional paternal information aside from solely providing the DNA 1 . Increasing evidence now suggests that sperm small non-coding RNAs (sncRNAs) can mediate intergenerational transmission of paternally acquired phenotypes, including mental stress 2,3 and metabolic disorders 4-6 . How sperm sncRNAs encode paternal information remains unclear, but the mechanism may involve RNA modifications. Here we show that deletion of a mouse tRNA methyltransferase, DNMT2, abolished sperm sncRNA-mediated transmission of high-fat-diet-induced metabolic disorders to offspring. Dnmt2 deletion prevented the elevation of RNA modifications (m 5 C, m 2 G) in sperm 30-40 nt RNA fractions that are induced by a high-fat diet. Also, Dnmt2 deletion altered the sperm small RNA expression profile, including levels of tRNA-derived small RNAs and rRNA-derived small RNAs, which might be essential in composing a sperm RNA 'coding signature' that is needed for paternal epigenetic memory. Finally, we show that Dnmt2-mediated m 5 C contributes to the secondary structure and biological properties of sncRNAs, implicating sperm RNA modifications as an additional layer of paternal hereditary information.
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U2 - 10.1038/s41556-018-0087-2
DO - 10.1038/s41556-018-0087-2
M3 - Article
C2 - 29695786
AN - SCOPUS:85046007423
VL - 20
SP - 535
EP - 540
JO - Nature Cell Biology
JF - Nature Cell Biology
SN - 1465-7392
IS - 5
ER -