Loss of DNMT1o disrupts imprinted X chromosome inactivation and accentuates placental defects in females.
Loss of DNMT1o disrupts imprinted X chromosome inactivation and accentuates placental defects in females.
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DOI：
10.1371/journal.pgen.1003873
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发表时间：
2013-11
期刊：
影响因子：
4.5
通讯作者：
Trasler JM
中科院分区：
文献类型：
--
作者：
McGraw S;Oakes CC;Martel J;Cirio MC;de Zeeuw P;Mak W;Plass C;Bartolomei MS;Chaillet JR;Trasler JM
在着床前发育过程中，关键的生殖细胞DNA甲基化模式的维持依赖于卵母细胞提供的DNA胞嘧啶甲基转移酶-1o（DNMT 1 o）的储存。Dnmt 1 Δ 1 o/Δ 1 o雌性小鼠所生的Dnmt 1 omat −/−小鼠胚胎缺乏DNMT 1 o蛋白，并具有破坏的基因组印记和相关的表型异常。在这里，我们描述了额外的女性特有的形态异常和DNA低甲基化缺陷以外的印记位点，仅限于胚外组织。与雄性后代相比，Dnmt 1 Δ 1 o/Δ 1 o母亲的雌性后代的胎盘显示出更高的基因和基因间低甲基化发生率以及更频繁和极端的胎盘畸形。大多数受影响的位点集中在X染色体上，并与异常的双等位基因表达相关，表明印记X失活受到干扰。低甲基化的Xite内的X-失活中心的一个关键调控区域存在于女性囊胚后不久，在8细胞阶段的甲基化维护DNMT 1 o的情况下。与母体DNMT 1 o缺乏相关的胎盘DNA低甲基化的女性优势提供了证据，证明了在植入前胚胎中DNA甲基化事件的基因组印记的维持之外的其他作用，包括印记X染色体失活的作用。在卵母细胞生长和成熟过程中，产生重要的蛋白质和酶，以确保受精时产生健康的胚胎。当这个自然过程被中断时，这些基本元素中的一种或多种可能无法产生，从而损害未来胚胎的健康。我们使用的是小鼠模型，缺乏卵母细胞中产生的酶（DNMT 1 o），只需要在早期胚胎中受精后维持遗传的DNA甲基化标记。在这里，我们发现，卵母细胞缺乏DNMT 10，受精时，产生的概念与各种各样的胎盘异常。这些胎盘异常在女性中更频繁和严重，并显示特定的基因组区域不断被剥夺其正常的甲基化标记。受影响的基因组区域集中在X染色体上。有趣的是，我们还发现，一个区域的X染色体失活过程的调节是低甲基化的女性囊胚，并与性别特异性异常的胎盘，放松印记X染色体失活，和DNA甲基化的破坏以后的发展。我们的研究结果提供了一个新的DNA甲基化事件发生在生命的最初几天内，特别是在女性植入前胚胎中的意想不到的作用。
The maintenance of key germline derived DNA methylation patterns during preimplantation development depends on stores of DNA cytosine methyltransferase-1o (DNMT1o) provided by the oocyte. Dnmt1omat−/− mouse embryos born to Dnmt1Δ1o/Δ1o female mice lack DNMT1o protein and have disrupted genomic imprinting and associated phenotypic abnormalities. Here, we describe additional female-specific morphological abnormalities and DNA hypomethylation defects outside imprinted loci, restricted to extraembryonic tissue. Compared to male offspring, the placentae of female offspring of Dnmt1Δ1o/Δ1o mothers displayed a higher incidence of genic and intergenic hypomethylation and more frequent and extreme placental dysmorphology. The majority of the affected loci were concentrated on the X chromosome and associated with aberrant biallelic expression, indicating that imprinted X-inactivation was perturbed. Hypomethylation of a key regulatory region of Xite within the X-inactivation center was present in female blastocysts shortly after the absence of methylation maintenance by DNMT1o at the 8-cell stage. The female preponderance of placental DNA hypomethylation associated with maternal DNMT1o deficiency provides evidence of additional roles beyond the maintenance of genomic imprints for DNA methylation events in the preimplantation embryo, including a role in imprinted X chromosome inactivation. During oocyte growth and maturation, vital proteins and enzymes are produced to ensure that, when fertilized, a healthy embryo will arise. When this natural process is interrupted, one or more of these essential elements can fail to be produced thus compromising the health of the future embryo. We are using a mouse model, lacking an enzyme (DNMT1o) produced in the oocyte and only required post-fertilization in the early embryo for the maintenance of inherited DNA methylation marks. Here, we reveal that oocytes lacking DNMT1o, when fertilized, generated conceptuses with a wide variety of placental abnormalities. These placental abnormalities were more frequent and severe in females, and showed specific genomic regions constantly deprived of their normal methylation marks. The affected genomic regions were concentrated on the X chromosome. Interestingly, we also found that a region important for the regulation of the X chromosome inactivation process was hypomethylated in female blastocysts and was associated with sex-specific abnormalities in the placenta, relaxation of imprinted X chromosome inactivation, and disruption of DNA methylation later in development. Our findings provide a novel unanticipated role for DNA methylation events taking place within the first few days of life specifically in female preimplantation embryos.
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影响因子：
10.5
作者：
BEARD, C;LI, E;JAENISCH, R
通讯作者：
JAENISCH, R
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10.5
作者：
CARLSON, LL;PAGE, AW;BESTOR, TH
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BESTOR, TH
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56.9
作者：
Bourc'his, D;Xu, GL;Bestor, TH
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2.7
作者：
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5.3
作者：
Boumil, RM;Ogawa, Y;Lee, JT
通讯作者：
Lee, JT