Loss of maternal CTCF is associated with peri-implantation lethality of Ctcf null embryos.
Loss of maternal CTCF is associated with peri-implantation lethality of Ctcf null embryos.
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DOI：
10.1371/journal.pone.0034915
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Filippova GN
中科院分区：
文献类型：
--
作者：
Moore JM;Rabaia NA;Smith LE;Fagerlie S;Gurley K;Loukinov D;Disteche CM;Collins SJ;Kemp CJ;Lobanenkov VV;Filippova GN
CTCF是一种高度保守的多功能锌指蛋白，参与基因调控的关键方面，包括转录调控、染色质绝缘、基因组印迹、x染色体失活和高阶染色质组织。CTCF的这种多功能特性表明它在发育中起着重要作用。事实上，之前一份关于母体CTCF耗竭的报告表明，CTCF对着床前发育至关重要。为了区分母体和合子CTCF表达的影响，我们研究了CTCF敲除等位基因完全丧失功能的小鼠着床前发育。尽管我们证明了Ctcf纯合缺失是早期胚胎致命的，但与之前的观察结果相反，我们发现Ctcf无合子胚胎发育到囊胚期（E3.5），随后是着床期致死（E4.5-E5.5）。体外培养的单细胞期Ctcf失合胚发育至16-32细胞期无明显异常。通过对同一胚胎进行基因型和mRNA表达分析的单胚胎实验，我们证明了Ctcf无合子胚胎的着床前发育与母体野生型Ctcf mRNA的保留有关。这种稳定的母体转录物的缺失与CTCF蛋白表达的缺失、发育中的胚胎的凋亡以及体外不能进一步发育内细胞团和滋养外胚层有关。这表明CTCF的表达对早期胚胎发生至关重要，其表达的缺失会在非常早期的发育阶段迅速导致细胞凋亡。这是第一个记录在囊胚期胚胎中存在稳定母体Ctcf转录本的研究。此外，在母体CTCF存在的情况下，受精卵CTCF的表达似乎不需要着床前发育。
CTCF is a highly conserved, multifunctional zinc finger protein involved in critical aspects of gene regulation including transcription regulation, chromatin insulation, genomic imprinting, X-chromosome inactivation, and higher order chromatin organization. Such multifunctional properties of CTCF suggest an essential role in development. Indeed, a previous report on maternal depletion of CTCF suggested that CTCF is essential for pre-implantation development. To distinguish between the effects of maternal and zygotic expression of CTCF, we studied pre-implantation development in mice harboring a complete loss of function Ctcf knockout allele. Although we demonstrated that homozygous deletion of Ctcf is early embryonically lethal, in contrast to previous observations, we showed that the Ctcf nullizygous embryos developed up to the blastocyst stage (E3.5) followed by peri-implantation lethality (E4.5–E5.5). Moreover, one-cell stage Ctcf nullizygous embryos cultured ex vivo developed to the 16–32 cell stage with no obvious abnormalities. Using a single embryo assay that allowed both genotype and mRNA expression analyses of the same embryo, we demonstrated that pre-implantation development of the Ctcf nullizygous embryos was associated with the retention of the maternal wild type Ctcf mRNA. Loss of this stable maternal transcript was temporally associated with loss of CTCF protein expression, apoptosis of the developing embryo, and failure to further develop an inner cell mass and trophoectoderm ex vivo. This indicates that CTCF expression is critical to early embryogenesis and loss of its expression rapidly leads to apoptosis at a very early developmental stage. This is the first study documenting the presence of the stable maternal Ctcf transcript in the blastocyst stage embryos. Furthermore, in the presence of maternal CTCF, zygotic CTCF expression does not seem to be required for pre-implantation development.
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