Stella safeguards the oocyte methylome by preventing de novo methylation mediated by DNMT1

Yingfeng Li; Zhuqiang Zhang; Jiayu Chen; Wenqiang Liu; Weiyi Lai; Baodong Liu; Xiang Li; Liping Liu; Shaohua Xu; Qiang Dong; Mingzhu Wang; Xiaoya Duan; Jiajun Tan; Yong Zheng; Pumin Zhang; Guoping Fan; Jiemin Wong; Guoliang Xu; Zhigao Wang; Hailin Wang; Shaorong Gao; Bing Zhu

doi:10.1038/s41586-018-0751-5

Stella safeguards the oocyte methylome by preventing de novo methylation mediated by DNMT1

Yingfeng Li
, Zhuqiang Zhang
, Jiayu Chen
, Wenqiang Liu
, Weiyi Lai
, Baodong Liu
, Xiang Li
, Liping Liu
, Shaohua Xu
, Qiang Dong
, Mingzhu Wang
, Xiaoya Duan
, Jiajun Tan
, Yong Zheng
, Pumin Zhang
, Guoping Fan
, Jiemin Wong
, Guoliang Xu
, Zhigao Wang
, Hailin Wang

Shaorong Gao, Bing Zhu

Research output: Contribution to journal › Article › peer-review

246 Citations (Scopus)

Abstract

Postnatal growth of mammalian oocytes is accompanied by a progressive gain of DNA methylation, which is predominantly mediated by DNMT3A, a de novo DNA methyltransferase^1,2. Unlike the genome of sperm and most somatic cells, the oocyte genome is hypomethylated in transcriptionally inert regions^2–4. However, how such a unique feature of the oocyte methylome is determined and its contribution to the developmental competence of the early embryo remains largely unknown. Here we demonstrate the importance of Stella, a factor essential for female fertility^5–7, in shaping the oocyte methylome in mice. Oocytes that lack Stella acquire excessive DNA methylation at the genome-wide level, including in the promoters of inactive genes. Such aberrant hypermethylation is partially inherited by two-cell-stage embryos and impairs zygotic genome activation. Mechanistically, the loss of Stella leads to ectopic nuclear accumulation of the DNA methylation regulator UHRF1^8,9, which results in the mislocalization of maintenance DNA methyltransferase DNMT1 in the nucleus. Genetic analysis confirmed the primary role of UHRF1 and DNMT1 in generating the aberrant DNA methylome in Stella-deficient oocytes. Stella therefore safeguards the unique oocyte epigenome by preventing aberrant de novo DNA methylation mediated by DNMT1 and UHRF1.

Original language	English
Pages (from-to)	136-140 (2018)
Number of pages	5
Journal	Nature
Volume	564
Issue number	7734
Early online date	28 Nov 2018
DOIs	https://doi.org/10.1038/s41586-018-0751-5
Publication status	Published (in print/issue) - 6 Dec 2018

Funding

Acknowledgements The Stella−/− mice were provided by the RIKEN BRC through the National Bio-Resource Project of the MEXT, Japan, and they were initially deposited by T. Nakamura and T. Nakano. We thank staff from the Laboratory Animal Research Center for technical assistance. We thank X. Wang, Z. Shen and H. Huang for discussion. This work was primarily supported by the China National Science Foundation (31521002), and was also supported by the Chinese Ministry of Science and Technology (2015CB856200, 2016YFA0100400 and 2017YFA0504200), the Chinese Academy of Sciences (XDB08010103, XDBP10 and QYZDY-SSW-SMC031), the China National Science Foundation (31425013, 31530037, 31730047, 31721003, 31871446 and31871448), the Shanghai Chenguang Program (16CG17) and the Shanghai Municipal Medical and Health Discipline Construction Projects (2017ZZ02015). Z.Z. is sponsored by the Youth Innovation Promotion Association (2017133) of the Chinese Academy of Sciences. G.F. is supported by the National Institutes of Health (R01DE025474).

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Keywords

Oocyte Genome
Major Satellite Repeats
Bisulfite Sanger Sequencing
Spindle-chromosome Complex
Media Assets

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10.1038/s41586-018-0751-5

Cite this

@article{c30150652f1144edb4117811f277ef7a,

title = "Stella safeguards the oocyte methylome by preventing de novo methylation mediated by DNMT1",

abstract = "Postnatal growth of mammalian oocytes is accompanied by a progressive gain of DNA methylation, which is predominantly mediated by DNMT3A, a de novo DNA methyltransferase1,2. Unlike the genome of sperm and most somatic cells, the oocyte genome is hypomethylated in transcriptionally inert regions2–4. However, how such a unique feature of the oocyte methylome is determined and its contribution to the developmental competence of the early embryo remains largely unknown. Here we demonstrate the importance of Stella, a factor essential for female fertility5–7, in shaping the oocyte methylome in mice. Oocytes that lack Stella acquire excessive DNA methylation at the genome-wide level, including in the promoters of inactive genes. Such aberrant hypermethylation is partially inherited by two-cell-stage embryos and impairs zygotic genome activation. Mechanistically, the loss of Stella leads to ectopic nuclear accumulation of the DNA methylation regulator UHRF18,9, which results in the mislocalization of maintenance DNA methyltransferase DNMT1 in the nucleus. Genetic analysis confirmed the primary role of UHRF1 and DNMT1 in generating the aberrant DNA methylome in Stella-deficient oocytes. Stella therefore safeguards the unique oocyte epigenome by preventing aberrant de novo DNA methylation mediated by DNMT1 and UHRF1.",

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author = "Yingfeng Li and Zhuqiang Zhang and Jiayu Chen and Wenqiang Liu and Weiyi Lai and Baodong Liu and Xiang Li and Liping Liu and Shaohua Xu and Qiang Dong and Mingzhu Wang and Xiaoya Duan and Jiajun Tan and Yong Zheng and Pumin Zhang and Guoping Fan and Jiemin Wong and Guoliang Xu and Zhigao Wang and Hailin Wang and Shaorong Gao and Bing Zhu",

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doi = "10.1038/s41586-018-0751-5",

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Li, Y, Zhang, Z, Chen, J, Liu, W, Lai, W, Liu, B, Li, X, Liu, L, Xu, S, Dong, Q, Wang, M, Duan, X, Tan, J, Zheng, Y, Zhang, P, Fan, G, Wong, J, Xu, G, Wang, Z, Wang, H, Gao, S & Zhu, B 2018, 'Stella safeguards the oocyte methylome by preventing de novo methylation mediated by DNMT1', Nature, vol. 564, no. 7734, pp. 136-140 (2018). https://doi.org/10.1038/s41586-018-0751-5

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T1 - Stella safeguards the oocyte methylome by preventing de novo methylation mediated by DNMT1

AU - Li, Yingfeng

AU - Zhang, Zhuqiang

AU - Chen, Jiayu

AU - Liu, Wenqiang

AU - Lai, Weiyi

AU - Liu, Baodong

AU - Li, Xiang

AU - Liu, Liping

AU - Xu, Shaohua

AU - Dong, Qiang

AU - Wang, Mingzhu

AU - Duan, Xiaoya

AU - Tan, Jiajun

AU - Zheng, Yong

AU - Zhang, Pumin

AU - Fan, Guoping

AU - Wong, Jiemin

AU - Xu, Guoliang

AU - Wang, Zhigao

AU - Wang, Hailin

AU - Gao, Shaorong

AU - Zhu, Bing

PY - 2018/12/6

Y1 - 2018/12/6

N2 - Postnatal growth of mammalian oocytes is accompanied by a progressive gain of DNA methylation, which is predominantly mediated by DNMT3A, a de novo DNA methyltransferase1,2. Unlike the genome of sperm and most somatic cells, the oocyte genome is hypomethylated in transcriptionally inert regions2–4. However, how such a unique feature of the oocyte methylome is determined and its contribution to the developmental competence of the early embryo remains largely unknown. Here we demonstrate the importance of Stella, a factor essential for female fertility5–7, in shaping the oocyte methylome in mice. Oocytes that lack Stella acquire excessive DNA methylation at the genome-wide level, including in the promoters of inactive genes. Such aberrant hypermethylation is partially inherited by two-cell-stage embryos and impairs zygotic genome activation. Mechanistically, the loss of Stella leads to ectopic nuclear accumulation of the DNA methylation regulator UHRF18,9, which results in the mislocalization of maintenance DNA methyltransferase DNMT1 in the nucleus. Genetic analysis confirmed the primary role of UHRF1 and DNMT1 in generating the aberrant DNA methylome in Stella-deficient oocytes. Stella therefore safeguards the unique oocyte epigenome by preventing aberrant de novo DNA methylation mediated by DNMT1 and UHRF1.

AB - Postnatal growth of mammalian oocytes is accompanied by a progressive gain of DNA methylation, which is predominantly mediated by DNMT3A, a de novo DNA methyltransferase1,2. Unlike the genome of sperm and most somatic cells, the oocyte genome is hypomethylated in transcriptionally inert regions2–4. However, how such a unique feature of the oocyte methylome is determined and its contribution to the developmental competence of the early embryo remains largely unknown. Here we demonstrate the importance of Stella, a factor essential for female fertility5–7, in shaping the oocyte methylome in mice. Oocytes that lack Stella acquire excessive DNA methylation at the genome-wide level, including in the promoters of inactive genes. Such aberrant hypermethylation is partially inherited by two-cell-stage embryos and impairs zygotic genome activation. Mechanistically, the loss of Stella leads to ectopic nuclear accumulation of the DNA methylation regulator UHRF18,9, which results in the mislocalization of maintenance DNA methyltransferase DNMT1 in the nucleus. Genetic analysis confirmed the primary role of UHRF1 and DNMT1 in generating the aberrant DNA methylome in Stella-deficient oocytes. Stella therefore safeguards the unique oocyte epigenome by preventing aberrant de novo DNA methylation mediated by DNMT1 and UHRF1.

KW - Oocyte Genome

KW - Major Satellite Repeats

KW - Bisulfite Sanger Sequencing

KW - Spindle-chromosome Complex

KW - Media Assets

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UR - https://pure.ulster.ac.uk/en/publications/stella-safeguards-the-oocyte-methylome-by-preventing-de-novo-meth

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DO - 10.1038/s41586-018-0751-5

M3 - Article

C2 - 30487604

AN - SCOPUS:85057727587

SN - 0028-0836

VL - 564

SP - 136-140 (2018)

JO - Nature

JF - Nature

IS - 7734

ER -

Stella safeguards the oocyte methylome by preventing de novo methylation mediated by DNMT1

Abstract

Funding

UN SDGs

Keywords

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