A genome-wide screen for modifiers of transgene variegation identifies genes with critical roles in development.
A genome-wide screen for modifiers of transgene variegation identifies genes with critical roles in development.
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DOI：
10.1186/gb-2008-9-12-r182
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发表时间：
2008
期刊：
影响因子：
12.3
通讯作者：
Whitelaw, Emma
中科院分区：
文献类型：
--
作者：
Ashe, Alyson;Morgan, Daniel K.;Whitelaw, Nadia C.;Bruxner, Timothy J.;Vickaryous, Nicola K.;Cox, Liza L.;Butterfield, Natalie C.;Wicking, Carol;Blewitt, Marnie E.;Wilkins, Sarah J.;Anderson, Gregory J.;Cox, Timothy C.;Whitelaw, Emma
对转基因杂色修饰剂的扩展ENU筛选鉴定了四种新的修饰剂，MommeD 7-D10。几年前，我们建立了一个N-乙基-N-亚硝基脲筛选小鼠转基因杂色的修饰剂，并发表了对前六个突变系的初步描述，命名为MommeD 1-D 6。我们已经报道了三个病例的潜在基因：MommeD 1是SMC铰链结构域1（Smchd 1）的突变，Smchd 1是一种新的表观遗传基因沉默修饰剂; MommeD 2是DNA甲基转移酶1（Dnmt 1）的突变; MommeD 4是斯马卡5（Snf 2 h）的突变，Snf 2 h是一种已知的染色质重塑剂。Dnmt 1和Smarca 5的识别证明了屏幕设计的有效性。我们现在已经扩展了屏幕，并确定了四个新的修改器，MommeD 7-D10。在这里，我们表明，所有10个MommeDs链接到基因组中的独特位点，突变的纯合性与严重的发育异常和杂合性导致表型异常，在某些情况下降低生殖适应性。此外，我们现在已经确定了MommeD 5和MommeD 10的潜在基因。MommeD 5是Hdac 1的突变，编码组蛋白脱乙酰酶1，MommeD 10是Baz 1b（也称为威廉姆斯综合征转录因子）的突变，编码含有PHD型锌指和溴结构域的转录因子。我们发现，小鼠Baz 1b水平的降低导致颅面特征让人联想到威廉姆斯综合征。这些结果证明了剂量依赖性表观遗传重编程在胚胎发育中的重要性，以及筛选提供小鼠模型来研究这一过程的能力。
An extended ENU screen for modifiers of transgene variegation identified four new modifiers, MommeD7-D10. Some years ago we established an N-ethyl-N-nitrosourea screen for modifiers of transgene variegation in the mouse and a preliminary description of the first six mutant lines, named MommeD1-D6, has been published. We have reported the underlying genes in three cases: MommeD1 is a mutation in SMC hinge domain containing 1 (Smchd1), a novel modifier of epigenetic gene silencing; MommeD2 is a mutation in DNA methyltransferase 1 (Dnmt1); and MommeD4 is a mutation in Smarca 5 (Snf2h), a known chromatin remodeler. The identification of Dnmt1 and Smarca5 attest to the effectiveness of the screen design. We have now extended the screen and have identified four new modifiers, MommeD7-D10. Here we show that all ten MommeDs link to unique sites in the genome, that homozygosity for the mutations is associated with severe developmental abnormalities and that heterozygosity results in phenotypic abnormalities and reduced reproductive fitness in some cases. In addition, we have now identified the underlying genes for MommeD5 and MommeD10. MommeD5 is a mutation in Hdac1, which encodes histone deacetylase 1, and MommeD10 is a mutation in Baz1b (also known as Williams syndrome transcription factor), which encodes a transcription factor containing a PHD-type zinc finger and a bromodomain. We show that reduction in the level of Baz1b in the mouse results in craniofacial features reminiscent of Williams syndrome. These results demonstrate the importance of dosage-dependent epigenetic reprogramming in the development of the embryo and the power of the screen to provide mouse models to study this process.
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影响因子：
64.5
作者：
Kitagawa, H;Fujiki, R;Kato, S
通讯作者：
Kato, S
影响因子：
2.5
作者：
Keays, David A.;Clark, Taane G.;Valdar, William
通讯作者：
Valdar, William
影响因子：
10.5
作者：
MCGOWAN, R;CAMPBELL, R;SAPIENZA, C
通讯作者：
SAPIENZA, C
影响因子：
30.8
作者：
Garrick, D;Fiering, S;Whitelaw, E
通讯作者：
Whitelaw, E
影响因子：
4
作者：
Edelmann, Lisa;Prosnitz, Aaron;McInnes, L. Alison
通讯作者：
McInnes, L. Alison