TY - JOUR
T1 - Maternal vitamin C regulates reprogramming of DNA methylation and germline development
AU - DiTroia, Stephanie P.
AU - Percharde, Michelle
AU - Guerquin, Marie Justine
AU - Wall, Estelle
AU - Collignon, Evelyne
AU - Ebata, Kevin T.
AU - Mesh, Kathryn
AU - Mahesula, Swetha
AU - Agathocleous, Michalis
AU - Laird, Diana J.
AU - Livera, Gabriel
AU - Ramalho-Santos, Miguel
N1 - Funding Information:
Acknowledgements We thank M. Conti, R. Blelloch, P. Rinaudo, M. Lorincz, S. Fisher, L. Selleri and members of the Santos laboratory for input and critical reading of the manuscript. We thank E. Chow and members of the UCSF Center for Advanced Technology for assistance with sequencing; B. Soygur for meiotic spread protocol and reagents; Y. Zhang and L. Shen for technical advice on RRBS. We are grateful to S. Henikoff for providing the pA-MN and yeast tRNA spike-ins, and to S. Henikoff and T. Fazzio for providing technical help with performing CUT&RUN experiments. Flow cytometry data were generated in the UCSF Parnassus Flow Cytometry Core, which is supported by a Diabetes Research Center grant and NIH grant P30 DK063720. S.P.D. was supported by the National Science Foundation Graduate Research Fellowship Program under grant no. 1650113. Any opinions, findings and conclusions or recommendations expressed in this material are those of the authors and do not necessarily reflect the views of the National Science Foundation. G.L. was partly supported by Institut Universitaire de France. This work was supported by National Institutes of Health (NIH) grants R21ES023297 and R01ES028212 to D.J.L., and NIH grants R01OD012204 and R01GM123556, and a Canada 150 Research Chair to M.R.-S.
Publisher Copyright:
© 2019, The Author(s), under exclusive licence to Springer Nature Limited.
PY - 2019/9/12
Y1 - 2019/9/12
N2 - Development is often assumed to be hardwired in the genome, but several lines of evidence indicate that it is susceptible to environmental modulation with potential long-term consequences, including in mammals1,2. The embryonic germline is of particular interest because of the potential for intergenerational epigenetic effects. The mammalian germline undergoes extensive DNA demethylation3–7 that occurs in large part by passive dilution of methylation over successive cell divisions, accompanied by active DNA demethylation by TET enzymes3,8–10. TET activity has been shown to be modulated by nutrients and metabolites, such as vitamin C11–15. Here we show that maternal vitamin C is required for proper DNA demethylation and the development of female fetal germ cells in a mouse model. Maternal vitamin C deficiency does not affect overall embryonic development but leads to reduced numbers of germ cells, delayed meiosis and reduced fecundity in adult offspring. The transcriptome of germ cells from vitamin-C-deficient embryos is remarkably similar to that of embryos carrying a null mutation in Tet1. Vitamin C deficiency leads to an aberrant DNA methylation profile that includes incomplete demethylation of key regulators of meiosis and transposable elements. These findings reveal that deficiency in vitamin C during gestation partially recapitulates loss of TET1, and provide a potential intergenerational mechanism for adjusting fecundity to environmental conditions.
AB - Development is often assumed to be hardwired in the genome, but several lines of evidence indicate that it is susceptible to environmental modulation with potential long-term consequences, including in mammals1,2. The embryonic germline is of particular interest because of the potential for intergenerational epigenetic effects. The mammalian germline undergoes extensive DNA demethylation3–7 that occurs in large part by passive dilution of methylation over successive cell divisions, accompanied by active DNA demethylation by TET enzymes3,8–10. TET activity has been shown to be modulated by nutrients and metabolites, such as vitamin C11–15. Here we show that maternal vitamin C is required for proper DNA demethylation and the development of female fetal germ cells in a mouse model. Maternal vitamin C deficiency does not affect overall embryonic development but leads to reduced numbers of germ cells, delayed meiosis and reduced fecundity in adult offspring. The transcriptome of germ cells from vitamin-C-deficient embryos is remarkably similar to that of embryos carrying a null mutation in Tet1. Vitamin C deficiency leads to an aberrant DNA methylation profile that includes incomplete demethylation of key regulators of meiosis and transposable elements. These findings reveal that deficiency in vitamin C during gestation partially recapitulates loss of TET1, and provide a potential intergenerational mechanism for adjusting fecundity to environmental conditions.
UR - http://www.scopus.com/inward/record.url?scp=85071946349&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85071946349&partnerID=8YFLogxK
U2 - 10.1038/s41586-019-1536-1
DO - 10.1038/s41586-019-1536-1
M3 - Article
C2 - 31485074
AN - SCOPUS:85071946349
SN - 0028-0836
VL - 573
SP - 271
EP - 275
JO - Nature
JF - Nature
IS - 7773
ER -