Deletion of CTCF sites in the SHH locus alters enhancer-promoter interactions and leads to acheiropodia.
Deletion of CTCF sites in the SHH locus alters enhancer-promoter interactions and leads to acheiropodia.
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SHH基因座中CTCF位点的缺失改变了增强子-启动子相互作用并导致无足畸形。
DOI：
10.1038/s41467-021-22470-z
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发表时间：
2021-04-16
影响因子：
16.6
通讯作者：
Ahituv N
中科院分区：
文献类型：
--
作者：
Ushiki A;Zhang Y;Xiong C;Zhao J;Georgakopoulos-Soares I;Kane L;Jamieson K;Bamshad MJ;Nickerson DA;University of Washington Center for Mendelian Genomics;Shen Y;Lettice LA;Silveira-Lucas EL;Petit F;Ahituv N
Acheiropodia是一种先天性肢体截肢，与ZRs周围LMBR1基因的纯合缺失有关，ZRs是一种在肢体发育过程中调节SHH的增强子。这些缺失是如何导致这种表型的尚不清楚。使用全基因组测序，我们将无虹足相关区域精细定位到12 kb，并表明它不起增强子的作用。CTCF和RAD21 CHIP-SEQ与4C-SEQ和DNA FISH一起确定了无头足缺失区域中的三个CTCF位点，它们介导了ZRs和SHH启动子之间的相互作用。这种相互作用被疾病状态下与ZRs着丝粒的其他CTCF位点所取代。小鼠对同源12 kb序列的敲除没有明显的异常，这表明由于物种之间固有的基序差异，在动物模型中模拟CTCFs变化是一项挑战。我们的结果表明，由于增强子-启动子相互作用的改变，CTCF基序的变化可以导致孟德尔条件。Acheiropodia与ZRS周围的LMBR1基因纯合缺失有关，ZRS是调节肢体发育过程中SHH的增强子，但这些缺失如何导致这种表型尚不清楚。在这里，作者使用全基因组测序、芯片序列、4C-序列和DNA FISH来证明CTCF基序的变化是通过改变增强子-启动子相互作用来实现的。
Acheiropodia, congenital limb truncation, is associated with homozygous deletions in the LMBR1 gene around ZRS, an enhancer regulating SHH during limb development. How these deletions lead to this phenotype is unknown. Using whole-genome sequencing, we fine-mapped the acheiropodia-associated region to 12 kb and show that it does not function as an enhancer. CTCF and RAD21 ChIP-seq together with 4C-seq and DNA FISH identify three CTCF sites within the acheiropodia-deleted region that mediate the interaction between the ZRS and the SHH promoter. This interaction is substituted with other CTCF sites centromeric to the ZRS in the disease state. Mouse knockouts of the orthologous 12 kb sequence have no apparent abnormalities, showcasing the challenges in modelling CTCF alterations in animal models due to inherent motif differences between species. Our results show that alterations in CTCF motifs can lead to a Mendelian condition due to altered enhancer–promoter interactions. Acheiropodia is associated with homozygous deletions in the LMBR1 gene around ZRS, an enhancer regulating SHH during limb development, but how these deletions lead to this phenotype is unknown. Here the authors use whole-genome sequencing, ChIP-seq, 4C-seq and DNA FISH to show that alterations in CTCF motifs are responsible via altered enhancer–promoter interactions.
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DOI：
10.1093/bioinformatics/btr064
发表时间：
2011-04-01
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Grant CE;Bailey TL;Noble WS
通讯作者：
Noble WS
影响因子：
64.5
作者：
Dowen JM;Fan ZP;Hnisz D;Ren G;Abraham BJ;Zhang LN;Weintraub AS;Schujiers J;Lee TI;Zhao K;Young RA
通讯作者：
Young RA
影响因子：
64.8
作者：
Karczewski, Konrad J;Francioli, Laurent C;MacArthur, Daniel G
通讯作者：
MacArthur, Daniel G
影响因子：
23.9
作者：
Ji X;Dadon DB;Powell BE;Fan ZP;Borges-Rivera D;Shachar S;Weintraub AS;Hnisz D;Pegoraro G;Lee TI;Misteli T;Jaenisch R;Young RA
通讯作者：
Young RA
影响因子：
4.6
作者：
Amemiya, Haley M.;Kundaje, Anshul;Boyle, Alan P.
通讯作者：
Boyle, Alan P.