Abstract
Uterine deficiency of Dnmt3b impairs decidualization and consequent embryo implantation defects. Recent advances in molecular technologies have allowed the unprecedented mapping of epigenetic modifications during embryo implantation. DNA methyltransferase 3a (DNMT3A) and DNMT3B are responsible for establishing DNA methylation patterns produced through their de novo-type DNA methylation activity in implantation stage embryos and during germ cell differentiation. It was reported that conditional knockout of Dnmt3a in the uterus does not markedly affect endometrial function during embryo implantation, but the tissue-specific functions of Dnmt3b in the endometrium during embryo implantation remain poorly understood to investigate the role of Dnmt3b during peri-implantation period. Here, we generated Dnmt3b conditional knockout (Dnmt3bd/d) female mice using progesterone receptor-Cre mice and examined the role of Dnmt3b during embryo implantation. Dnmt3bd/d female mice exhibited compromised fertility, which was associated with defective decidualization, but not endometrial receptivity. Furthermore, results showed loss of Dnmt3b did not lead to altered genomic methylation patterns of the decidual endometrium during early pregnancy. Transcriptome sequencing analysis of uteri from day 6 pregnant mice identified phosphoglycerate kinase 1 (Pgk1) as one of the most variable genes in Dnmt3bd/d decidual endometrium. Potential roles of PGK1 in the decidualization process during early pregnancy were confirmed. Lastly, the compromised decidualization upon the downregulation of Dnmt3b could be reversed by overexpression of Pgk1. Collectively, our findings indicate that uterine deficiency of Dnmt3b impairs decidualization and consequent embryo implantation defects.
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1. Dnmt3bd/d female mice exhibited compromised fertility, which was associated with defective decidualization, but not endometrial receptivity. 2. Losing Dnmt3b did not alter genomic methylation patterns of the decidual endometrium during early pregnancy. 3. Pgk1 was one of the most variable genes in Dnmt3bd/d decidual endometrium and the compromised decidualization upon the downregulation of Dnmt3b was related to the overexpression of Pgk1.
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Funding
This work was supported by the National Key Research and Development Program of China [2018YFC1004401], the Natural Science Foundation of Chongqing [cstc2018jcyjAX0309], and the Science and Technology Research Program of Chongqing Municipal Education Commission [KJQN201900413].
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YW and RG designed and directed the study. JL and MC performed the analyses and interpretation of data. RG and JL wrote and critically reviewed the manuscript. YW and YD conceived the study. JL and WL performed experiments, the analyses and interpretation of data. MC performed experiments and analyzed data. CT provided technical and study design support. XC, CP, FL provided technical and material support. NL, XL, JH, YG, TL, and XM provided technical support.
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Long, J., Li, W., Chen, M. et al. Uterine deficiency of Dnmt3b impairs decidualization and causes consequent embryo implantation defects. Cell Biol Toxicol 39, 1077–1098 (2023). https://doi.org/10.1007/s10565-021-09664-3
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DOI: https://doi.org/10.1007/s10565-021-09664-3