Loss of inherited genomic imprints in mice leads to severe disruption in placental lipid metabolism.
Loss of inherited genomic imprints in mice leads to severe disruption in placental lipid metabolism.
复制标题
DOI：
10.1016/j.placenta.2015.01.012
复制
发表时间：
2015-04
期刊：
影响因子：
3.8
通讯作者：
Chaillet, J. R.
中科院分区：
文献类型：
--
作者：
Himes, K. P.;Young, A.;Koppes, E.;Stolz, D.;Barak, Y.;Sadovsky, Y.;Chaillet, J. R.
印记基因的单等位基因表达是胎盘发育和胎儿正常生长所必需的。差异甲基化区域(DMD)在很大程度上决定了印记基因的亲本特异性单等位基因表达。母系来源的DNA(胞嘧啶-5-)甲基转移酶10(DNMT10)在8细胞发育阶段维持DMD。DNMT10基因缺陷的小鼠胎盘具有广泛的基因组印记破坏。以往的研究表明，DNMT1o缺乏症会改变胎盘的形态，扩大妊娠晚期胚胎的体重分布。血脂对胎儿的生长发育至关重要。因此，我们评估了干扰印迹对胎盘脂质的影响。用一种改进的Folch方法对DNMT10缺陷小鼠胎盘和胚胎的脂质进行了定量。选择脂代谢关键基因的表达用RT-qPCR进行定量。用透射电子显微镜观察线粒体形态，定量测定线粒体乌头酸酶和胞浆柠檬酸浓度。用EpiTYPER法检测DMD甲基化。我们发现DNMT1o缺乏症与胎盘三酰甘油水平升高有关。无论是胎儿的三酰甘油浓度还是介导胎盘脂肪运输的特定基因的表达都与野生型不同。胎盘三酰甘油蓄积与β-氧化受损和柠檬酸代谢异常有关，线粒体乌头酸酶活性降低，胞浆柠檬酸浓度升高。MEST DMD的甲基化缺失与胎盘三酰甘油蓄积密切相关。基因组印迹的广泛破坏会导致三酰甘油的积累和线粒体功能的异常。这可能直接源于特定DMD的甲基化缺失，如MEST，或代表胎盘发育异常的结果。
Monoallelic expression of imprinted genes is necessary for placental development and normal fetal growth. Differentially methylated domains (DMDs) largely determine the parental-specific monoallelic expression of imprinted genes. Maternally derived DNA (cytosine-5-) -methyltransferase 1o (DNMT1o) maintains DMDs during the eight-cell stage of development. DNMT1o-deficient mouse placentas have a generalized disruption of genomic imprints. Previous studies have demonstrated that DNMT1o deficiency alters placental morphology and broadens the embryonic weight distribution in late gestation. Lipids are critical for fetal growth. Thus, we assessed the impact of disrupted imprinting on placental lipids. Lipids were quantified from DNMT1o-deficient mouse placentas and embryos at E17.5 using a modified Folch method. Expression of select genes critical for lipid metabolism was quantified with RT-qPCR. Mitochondrial morphology was assessed by TEM and mitochondrial aconitase and cytoplasmic citrate concentrations quantified. DMD methylation was determined by EpiTYPER. We found that DNMT1o deficiency is associated with increased placental triacylglycerol levels. Neither fetal triacylglycerol concentrations nor expression of select genes that mediate placental lipid transport were different from wild type. Placental triacylglycerol accumulation was associated with impaired beta-oxidation and abnormal citrate metabolism with decreased mitochondrial aconitase activity and increased cytoplasmic citrate concentrations. Loss of methylation at the MEST DMD was strongly associated with placental triacylglycerol accumulation. A generalized disruption of genomic imprints leads to triacylglycerol accumulation and abnormal mitochondrial function. This could stem directly from a loss of methylation at a given DMD, such as MEST, or represent a consequence of abnormal placental development.
登录
查看更多内容
影响因子：
4.5
作者：
Frost JM;Moore GE
通讯作者：
Moore GE
影响因子：
2.7
作者：
Doherty, AS;Bartolomei, MS;Schultz, RM
通讯作者：
Schultz, RM
影响因子：
4.8
作者：
Nikonova, Larissa;Koza, Robert A.;Kozak, Leslie P.
通讯作者：
Kozak, Leslie P.
影响因子：
--
作者：
Cirio MC;Ratnam S;Ding F;Reinhart B;Navara C;Chaillet JR
通讯作者：
Chaillet JR
影响因子：
3.8
作者：
Burton GJ;Yung HW;Cindrova-Davies T;Charnock-Jones DS
通讯作者：
Charnock-Jones DS