CTCF cis-regulates trinucleotide repeat instability in an epigenetic manner: a novel basis for mutational hot spot determination.
CTCF cis-regulates trinucleotide repeat instability in an epigenetic manner: a novel basis for mutational hot spot determination.
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DOI：
10.1371/journal.pgen.1000257
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发表时间：
2008-11
期刊：
影响因子：
4.5
通讯作者：
La Spada AR
中科院分区：
文献类型：
--
作者：
Libby RT;Hagerman KA;Pineda VV;Lau R;Cho DH;Baccam SL;Axford MM;Cleary JD;Moore JM;Sopher BL;Tapscott SJ;Filippova GN;Pearson CE;La Spada AR
人类至少有 25 种遗传性疾病是由微卫星重复扩增引起的。不同疾病位点和不同组织之间重复不稳定性存在显着差异；然而，调节不稳定过程的顺式因素和反式因素仍未明确。来自人类脊髓小脑共济失调 7 型 (SCA7) 基因座的基因组片段包含高度不稳定的 CAG 束，之前被引入小鼠体内以定位顺式作用的“不稳定元件”，并揭示了重复不稳定需要基因组背景。关键的不稳定诱导区域包含 CTCF 的结合位点，CTCF 是一种与基因组印记、染色质重塑和 DNA 构象变化有关的调节因子。为了评估 CTCF 在重复不稳定性中的作用，我们衍生了携带带有 CTCF 结合位点突变的 SCA7 基因组片段的转基因小鼠。我们发现 CTCF 结合位点突变会促进种系和体细胞组织中三联体重复的不稳定，并且 CTCF 结合位点的 CpG 甲基化可以进一步破坏三联体重复扩增的稳定性。由于 CTCF 结合位点与许多高度不稳定的重复位点相关，因此我们的研究结果为划分和调节突变热点提供了新的基础，并暗示 CTCF 参与了遗传重复不稳定性的调节。人类基因组包含许多重复序列。 1991年，我们发现三核苷酸（三核苷酸）重复序列的过度延长可能导致人类遗传疾病。我们现在知道，这种被称为“重复扩增”的独特基因突变发生在至少 25 种不同的疾病中，包括遗传性神经系统疾病，例如智力低下的脆性 X 综合征、强直性肌营养不良症和亨廷顿病。重复扩展突变的一个有趣特征是它们在遗传上不稳定，这意味着当从亲本传递给后代时，重复扩展的长度会发生变化。因此，扩展的重复序列违反了遗传学的一个主要原则，即任何给定的序列发生突变的可能性都很低。对于扩展重复，进一步突变的可能性接近 100%。了解为什么扩展的重复序列如此易变一直是遗传学研究的一个具有挑战性的问题。在这项研究中，我们通过证明扩展的重复序列旁边的 CTCF 结合位点的突变增加了小鼠的遗传不稳定性，从而表明 CTCF 蛋白参与了重复扩展过程。 CTCF是控制基因表达的重要调控因子。由于 CTCF 的结合位点与许多重复序列相关，因此 CTCF 可能在调节各种重复疾病的遗传不稳定性中发挥作用，而不仅仅是我们研究的疾病。
At least 25 inherited disorders in humans result from microsatellite repeat expansion. Dramatic variation in repeat instability occurs at different disease loci and between different tissues; however, cis-elements and trans-factors regulating the instability process remain undefined. Genomic fragments from the human spinocerebellar ataxia type 7 (SCA7) locus, containing a highly unstable CAG tract, were previously introduced into mice to localize cis-acting “instability elements,” and revealed that genomic context is required for repeat instability. The critical instability-inducing region contained binding sites for CTCF—a regulatory factor implicated in genomic imprinting, chromatin remodeling, and DNA conformation change. To evaluate the role of CTCF in repeat instability, we derived transgenic mice carrying SCA7 genomic fragments with CTCF binding-site mutations. We found that CTCF binding-site mutation promotes triplet repeat instability both in the germ line and in somatic tissues, and that CpG methylation of CTCF binding sites can further destabilize triplet repeat expansions. As CTCF binding sites are associated with a number of highly unstable repeat loci, our findings suggest a novel basis for demarcation and regulation of mutational hot spots and implicate CTCF in the modulation of genetic repeat instability. The human genome contains many repetitive sequences. In 1991, we discovered that excessive lengthening of a three-nucleotide (trinucleotide) repeat sequence could cause a human genetic disease. We now know that this unique type of genetic mutation, known as a “repeat expansion,” occurs in at least 25 different diseases, including inherited neurological disorders such as the fragile X syndrome of mental retardation, myotonic muscular dystrophy, and Huntington's disease. An interesting feature of repeat expansion mutations is that they are genetically unstable, meaning that the repeat expansion changes in length when transmitted from parent to offspring. Thus, expanded repeats violate one major tenet of genetics—i.e., that any given sequence has a low likelihood for mutation. For expanded repeats, the likelihood of further mutation approaches 100%. Understanding why expanded repeats are so mutable has been a challenging problem for genetics research. In this study, we implicate the CTCF protein in the repeat expansion process by showing that mutation of a CTCF binding site, next to an expanded repeat sequence, increases genetic instability in mice. CTCF is an important regulatory factor that controls the expression of genes. As binding sites for CTCF are associated with many repeat sequences, CTCF may play a role in regulating genetic instability in various repeat diseases—not just the one we studied.
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CTCFL/BORIS是一种与甲基化无关的DNA结合蛋白，优先结合父亲H19差异甲基化区域。
影响因子：
11.2
作者：
Nguyen P;Cui H;Bisht KS;Sun L;Patel K;Lee RS;Kugoh H;Oshimura M;Feinberg AP;Gius D
通讯作者：
Gius D
影响因子：
3.5
作者：
Libby, RT;Monckton, DG;La Spada, AR
通讯作者：
La Spada, AR
影响因子：
3.5
作者：
Monckton, DG;Cayuela, ML;Ashizawa, T
通讯作者：
Ashizawa, T
影响因子：
3.5
作者：
Chen, SM;Peng, GH;La Spada, AR
通讯作者：
La Spada, AR
影响因子：
30.8
作者：
David, G;Abbas, N;Brice, A
通讯作者：
Brice, A