The Gpr1/Zdbf2 locus provides new paradigms for transient and dynamic genomic imprinting in mammals.
The Gpr1/Zdbf2 locus provides new paradigms for transient and dynamic genomic imprinting in mammals.
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DOI：
10.1101/gad.232058.113
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发表时间：
2014-03-01
影响因子：
10.5
通讯作者：
Bourc'his D
中科院分区：
文献类型：
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作者：
Duffié R;Ajjan S;Greenberg MV;Zamudio N;Escamilla del Arenal M;Iranzo J;Okamoto I;Barbaux S;Fauque P;Bourc'his D
在哺乳动物发育过程中，许多基因座仅在受精后短暂维持亲本 DNA 甲基化。这种形式的瞬时基因组印记是否会在功能上影响哺乳动物基因组调控尚不清楚。在这里，杜菲等人。描述了一种机制，通过该机制，小鼠 Gpr1/Zdbf2 基因座上的短暂母体印记调节早期胚胎中 Zdbf2 (Liz) 长亚型的父本特异性表达。这项研究证明了基因组印记对哺乳动物基因组调控的短期和长期影响的潜力。在哺乳动物发育过程中，许多基因座在受精后仅短暂维持母源 DNA 甲基化：这种形式的瞬时基因组印记是否会影响早期胚胎转录组，甚至对基因组调控和可能的表型产生终生影响，目前尚不清楚。在这里，我们报告了小鼠 Gpr1/Zdbf2（DBF 型锌指蛋白 2）位点的母系种系差异甲基化区域（DMR），该区域控制早期胚胎中 Zdbf2（Liz）长亚型的父本特异性表达。这种 DMR 在植入胚胎时由于 DNA 甲基化而失去了亲本特异性，但在胚胎外组织中得以维持。由于这种短暂的、组织特异性的母体印记，Liz 的表达仅限于多能胚胎、胚胎外组织和多能雄性生殖细胞。我们发现 Liz 可能同时具有 Zdbf2 编码 RNA 和顺式调节 RNA 的功能。重要的是，Liz 介导的事件允许在胚胎分化过程中从母本印记 DNA 甲基化转变为父本印记 DNA 甲基化，以及从 Liz 到规范 Zdbf2 启动子的使用，这些在体细胞生命中稳定维持并在人类中保守。 Gpr1/Zdbf2 基因座缺乏经典的印记组蛋白修饰，但对突变胚胎干细胞的分析揭示了通过 DNA 和 H3K27 甲基化相互作用对 Zdbf2 剂量进行微调。我们的工作共同强调了发育和进化的需要，以确保适当的 Liz/Zdbf2 剂量作为 Gpr1/Zdbf2 基因座动态基因组印记的驱动力。
Many loci maintain parent-of-origin DNA methylation only briefly after fertilization during mammalian development. Whether this form of transient genomic imprinting could functionally impact mammalian genome regulation is unknown. Here, Duffié et al. describe a mechanism by which a transient maternal imprint at the mouse Gpr1/Zdbf2 locus regulates the paternal-specific expression of long isoforms of Zdbf2 (Liz) in the early embryo. This study demonstrates the potential for short-term and long-term effects of genomic imprinting on mammalian genome regulation. Many loci maintain parent-of-origin DNA methylation only briefly after fertilization during mammalian development: Whether this form of transient genomic imprinting can impact the early embryonic transcriptome or even have life-long consequences on genome regulation and possibly phenotypes is currently unknown. Here, we report a maternal germline differentially methylated region (DMR) at the mouse Gpr1/Zdbf2 (DBF-type zinc finger-containing protein 2) locus, which controls the paternal-specific expression of long isoforms of Zdbf2 (Liz) in the early embryo. This DMR loses parental specificity by gain of DNA methylation at implantation in the embryo but is maintained in extraembryonic tissues. As a consequence of this transient, tissue-specific maternal imprinting, Liz expression is restricted to the pluripotent embryo, extraembryonic tissues, and pluripotent male germ cells. We found that Liz potentially functions as both Zdbf2-coding RNA and cis-regulatory RNA. Importantly, Liz-mediated events allow a switch from maternal to paternal imprinted DNA methylation and from Liz to canonical Zdbf2 promoter use during embryonic differentiation, which are stably maintained through somatic life and conserved in humans. The Gpr1/Zdbf2 locus lacks classical imprinting histone modifications, but analysis of mutant embryonic stem cells reveals fine-tuned regulation of Zdbf2 dosage through DNA and H3K27 methylation interplay. Together, our work underlines the developmental and evolutionary need to ensure proper Liz/Zdbf2 dosage as a driving force for dynamic genomic imprinting at the Gpr1/Zdbf2 locus.
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影响因子：
4.5
作者：
Kobayashi H;Sakurai T;Imai M;Takahashi N;Fukuda A;Yayoi O;Sato S;Nakabayashi K;Hata K;Sotomaru Y;Suzuki Y;Kono T
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影响因子：
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作者：
Ginno PA;Lott PL;Christensen HC;Korf I;Chédin F
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