Epigenetic and Phenotypic Consequences of a Truncation Disrupting the Imprinted Domain on Distal Mouse Chromosome 7
Epigenetic and Phenotypic Consequences of a Truncation Disrupting the Imprinted Domain on Distal Mouse Chromosome 7
复制标题
破坏远端小鼠 7 号染色体印记结构域的截断的表观遗传和表型后果
DOI：
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发表时间：
2007
影响因子：
5.3
通讯作者：
L. Lefebvre
中科院分区：
文献类型：
--
作者：
R. Oh;Rita Ho;L. Mar;M. Gertsenstein;J. Paděrová;J. Hsien;J. Squire;M. Higgins;A. Nagy;L. Lefebvre
摘要小鼠7号染色体远端(Chr7)含有一大簇印记基因。在该区域，两个顺式作用印迹中心IC1(H19DMR)和IC2(KvDMR1)分别定义近端和远端亚区。为了评估IC1在Chr 7背景下的功能独立性，我们在胚胎干细胞中开发了一种重组酶介导的染色体截断策略，并产生了一个末端缺失等位基因DelTel7，在两个亚域之间有一个断裂点。我们获得了截短的Chr7和存活的父本杂合子的种系传递，证实了Ins2远端缺乏发育所需的父本表达基因。相反，DelTel7的母体传播会导致中期死亡，这与IC2亚区母体表达基因的丢失一致。DelTel7杂合子的表达和DNA甲基化分析表明，在没有完整IC2亚域的情况下，IC1是独立印记的。因此，IC1在Chr 7上的印记不需要在进化上保守的亚区之间的连锁。重要的是，父系遗传的IC2缺失完全挽救了母体杂合子的发育表型。因此，位于该区域的正常发育所需的所有印记基因都被父亲等位基因上的IC2依赖机制沉默。
ABSTRACT The distal end of mouse chromosome 7 (Chr 7) contains a large cluster of imprinted genes. In this region two cis-acting imprinting centers, IC1 (H19 DMR) and IC2 (KvDMR1), define proximal and distal subdomains, respectively. To assess the functional independence of IC1 in the context of Chr 7, we developed a recombinase-mediated chromosome truncation strategy in embryonic stem cells and generated a terminal deletion allele, DelTel7, with a breakpoint in between the two subdomains. We obtained germ line transmission of the truncated Chr 7 and viable paternal heterozygotes, confirming the absence of developmentally required paternally expressed genes distal of Ins2. Conversely, maternal transmission of DelTel7 causes a midgestational lethality, consistent with loss of maternally expressed genes in the IC2 subdomain. Expression and DNA methylation analyses on DelTel7 heterozygotes demonstrate the independent imprinting of IC1 in absence of the entire IC2 subdomain. The evolutionarily conserved linkage between the subdomains is therefore not required for IC1 imprinting on Chr 7. Importantly, the developmental phenotype of maternal heterozygotes is rescued fully by a paternally inherited deletion of IC2. Thus, all the imprinted genes located in the region and required for normal development are silenced by an IC2-dependent mechanism on the paternal allele.
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DOI：
10.1073/pnas.91.19.8861
发表时间：
1994-09-13
影响因子：
11.1
作者：
HANISH, JP;YANOWITZ, JL;DELANGE, T
通讯作者：
DELANGE, T
影响因子：
4.6
作者：
K. McLaughlin;H. Kochanowski;D. Solter;G. Schwarzkopf;P. Szabó;J. Mann
通讯作者：
K. McLaughlin;H. Kochanowski;D. Solter;G. Schwarzkopf;P. Szabó;J. Mann
影响因子：
10.5
作者：
BARTOLOMEI, MS;WEBBER, AL;TILGHMAN, SM
通讯作者：
TILGHMAN, SM
影响因子：
10.5
作者：
Thorvaldsen, JL;Duran, KL;Bartolomei, MS
通讯作者：
Bartolomei, MS
影响因子：
4.4
作者：
Davis, TL;Trasler, JM;Bartolomei, MS
通讯作者：
Bartolomei, MS