TY - JOUR
T1 - Embryonic defects induced by maternal obesity in mice derive from Stella insufficiency in oocytes
AU - Han, Longsen
AU - Ren, Chao
AU - Li, Ling
AU - Li, Xiaoyan
AU - Ge, Juan
AU - Wang, Haichao
AU - Miao, Yi Liang
AU - Guo, Xuejiang
AU - Moley, Kelle H.
AU - Shu, Wenjie
AU - Wang, Qiang
N1 - Funding Information:
We are grateful to T. Schedl (Washington University in St. Louis School of Medicine) for a valuable discussion that led to the experiment design reported in this paper and his critical reading of the manuscript. We also thank Q.-Y. Sun and Z.-B. Wang (Chinese Academy of Sciences) for providing plasmids and Y.-S. Guo (Nanjing Medical University) for help with the proteomic assay. This work was supported by National Key Scientific Research Projects of China (2014CB943200 to Q.W.), the National Key Research and Development Program of China (2017YFC1001500 to Q.W.), the National Natural Science Foundation of China (no. 31571543 to Q.W.), a Major Research Plan of the National Natural Science Foundation of China (no. U1435222 to W.S.), a Major Research Plan of the National Key R&D Program of China (no. 2016YFC0901600 to W.S.), and the National High Technology Research and Development Program of China (no. 2015AA020108 to W.S.).
Publisher Copyright:
© 2018 The Author(s).
PY - 2018/3/1
Y1 - 2018/3/1
N2 - Maternal obesity can impair embryo development and offspring health, yet the mechanisms responsible remain poorly understood. In a high-fat diet (HFD)-based female mouse model of obesity, we identified a marked reduction of Stella (also known as DPPA3 or PGC7) protein in oocytes. Starting with this clue, we found that the establishment of pronuclear epigenetic asymmetry in zygotes from obese mice was severely disrupted, inducing the accumulation of maternal 5-hydroxymethylcytosine modifications and DNA lesions. Furthermore, methylome-wide sequencing analysis detected global hypomethylation across the zygote genome in HFD-fed mice, with a specific enrichment in transposon elements and unique regions. Notably, overexpression of Stella in the oocytes of HFD-fed mice not only restored the epigenetic remodeling in zygotes but also partly ameliorated the maternal-obesity-associated developmental defects in early embryos and fetal growth. Thus, Stella insufficiency in oocytes may represent a critical mechanism that mediates the phenotypic effects of maternal obesity in embryos and offspring.
AB - Maternal obesity can impair embryo development and offspring health, yet the mechanisms responsible remain poorly understood. In a high-fat diet (HFD)-based female mouse model of obesity, we identified a marked reduction of Stella (also known as DPPA3 or PGC7) protein in oocytes. Starting with this clue, we found that the establishment of pronuclear epigenetic asymmetry in zygotes from obese mice was severely disrupted, inducing the accumulation of maternal 5-hydroxymethylcytosine modifications and DNA lesions. Furthermore, methylome-wide sequencing analysis detected global hypomethylation across the zygote genome in HFD-fed mice, with a specific enrichment in transposon elements and unique regions. Notably, overexpression of Stella in the oocytes of HFD-fed mice not only restored the epigenetic remodeling in zygotes but also partly ameliorated the maternal-obesity-associated developmental defects in early embryos and fetal growth. Thus, Stella insufficiency in oocytes may represent a critical mechanism that mediates the phenotypic effects of maternal obesity in embryos and offspring.
UR - https://www.scopus.com/pages/publications/85042192275
U2 - 10.1038/s41588-018-0055-6
DO - 10.1038/s41588-018-0055-6
M3 - Article
C2 - 29459681
AN - SCOPUS:85042192275
SN - 1061-4036
VL - 50
SP - 432
EP - 442
JO - Nature Genetics
JF - Nature Genetics
IS - 3
ER -