Elevated RIF1 participates in the epigenetic abnormalities of zygotes by regulating histone modifications on MuERV-L in obese mice.
Elevated RIF1 participates in the epigenetic abnormalities of zygotes by regulating histone modifications on MuERV-L in obese mice.
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RIF1升高通过调节肥胖小鼠MuERV-L上的组蛋白修饰参与受精卵的表观遗传异常
DOI：
10.1186/s10020-022-00446-z
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发表时间：
2022-02-05
期刊：
影响因子：
--
通讯作者：
Li Z
中科院分区：
文献类型：
--
作者：
Huang J;Ru G;Sun J;Sun L;Li Z
研究背景母亲肥胖损害胚胎发育潜能，显著增加后代代谢紊乱的风险。然而，母体代谢异常的表观遗传传递机制仍然知之甚少。MethodsWe建立了一个肥胖模型的雌性小鼠高脂饮食（HFD）喂养。研究了HFD对卵母细胞和胚胎发育潜能、代谢表型和表观遗传修饰的影响。评估二甲双胍给药的疗效。最后，合子基因组激活（ZGA）过程中的表观遗传重塑的调节途径explored.ResultsMaternal HFD消费显着受损的葡萄糖耐量和F0和F1小鼠代谢紊乱的风险增加。母体HFD消耗还降低了胚胎发育潜力，增加了活性氧（ROS）和γ H2 AX水平，并降低了卵母细胞内的线粒体膜电位（MMP），导致高水平的氧化应激损伤和DNA损伤。从这个线索开始，我们观察到肥胖小鼠的RIF 1水平显著增加，端粒缩短。此外，在肥胖小鼠的ZGA过程中观察到显著的异常DNA甲基化和组蛋白修饰重塑，这可能是由RIF 1和ZGA标记基因MuERV-L共同调节的。二甲双胍治疗降低了RIF 1水平，并通过挽救肥胖小鼠卵母细胞和植入前胚胎中的表观遗传修饰重塑部分改善了ZGA激活状态。采用Trim-Away方法的RIF 1敲除实验表明，RIF 1降解改变了H3 K4 me 3和H3 K9 me 3的富集，然后触发MuERV-L转录激活。此外，RIF 1基因敲除的ChIP-seq数据分析也表明，RIF 1通过改变H3 K4 me 3和H3 K9 me 3的富集而不是通过改变DNA甲基化来介导MuERV-L的转录调控。结论母亲肥胖导致的卵母细胞中RIF 1升高可能通过调节MuERV-L上的组蛋白修饰介导异常的胚胎表观遗传重构并增加后代的代谢风险。其可通过二甲双胍治疗部分挽救。
BackgroundMaternal obesity impairs embryonic developmental potential and significantly increases the risks of metabolic disorders in offspring. However, the epigenetic transmission mechanism of maternal metabolic abnormalities is still poorly understood.MethodsWe established an obesity model in female mice by high-fat diet (HFD) feeding. The effects of the HFD on the developmental potential of oocytes and embryos, the metabolic phenotype, and epigenetic modifications were investigated. The efficacy of metformin administration was assessed. Finally, the regulatory pathway of epigenetic remodeling during zygotic genome activation (ZGA) was explored.ResultsMaternal HFD consumption significantly impaired glucose tolerance and increased the risk of metabolic disorders in F0 and F1 mice. Maternal HFD consumption also decreased embryonic developmental potential, increased reactive oxygen species (ROS) and γH2AX levels, and reduced the mitochondrial membrane potential (MMP) within oocytes, causing high levels of oxidative stress damage and DNA damage. Starting with this clue, we observed significantly increased RIF1 levels and shortened telomeres in obese mice. Moreover, significant abnormal DNA methylation and histone modification remodeling were observed during ZGA in obese mice, which may be coregulated by RIF1 and the ZGA marker gene MuERV-L. Metformin treatment reduced RIF1 levels, and partially improved ZGA activation status by rescuing epigenetic modification remodeling in oocytes and preimplantation embryos of obese mice. RIF1 knockdown experiments employing Trim-Away methods showed that RIF1 degradation altered the H3K4me3 and H3K9me3 enrichment and then triggered the MuERV-L transcriptional activation. Moreover, ChIP-seq data analysis of RIF1 knockouts also showed that RIF1 mediates the transcriptional regulation of MuERV-L by changing the enrichment of H3K4me3 and H3K9me3 rather than by altered DNA methylation.ConclusionElevated RIF1 in oocytes caused by maternal obesity may mediate abnormal embryonic epigenetic remodeling and increase metabolic risk in offspring by regulating histone modifications on MuERV-L, which can be partially rescued by metformin treatment.
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DOI：
10.1083/jcb.200902039
发表时间：
2009-11-02
期刊：
The Journal of cell biology
影响因子：
--
作者：
Buonomo SB;Wu Y;Ferguson D;de Lange T
通讯作者：
de Lange T
DOI：
10.1126/science.1230624
发表时间：
2013-02-08
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Di Virgilio M;Callen E;Yamane A;Zhang W;Jankovic M;Gitlin AD;Feldhahn N;Resch W;Oliveira TY;Chait BT;Nussenzweig A;Casellas R;Robbiani DF;Nussenzweig MC
通讯作者：
Nussenzweig MC
DOI：
10.1016/s2213-8587(16)30107-3
发表时间：
2017-01
期刊：
The lancet. Diabetes & endocrinology
影响因子：
--
作者：
Godfrey KM;Reynolds RM;Prescott SL;Nyirenda M;Jaddoe VW;Eriksson JG;Broekman BF
通讯作者：
Broekman BF
影响因子：
8
作者：
Cuyas, E.;Fernandez-Arroyo, S.;Menendez, J. A.
通讯作者：
Menendez, J. A.
影响因子：
64.8
作者：
Elsässer SJ;Noh KM;Diaz N;Allis CD;Banaszynski LA
通讯作者：
Banaszynski LA