Alu insertion variants alter gene transcript levels.
Alu insertion variants alter gene transcript levels.
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ALU插入变体改变了基因转录水平。
DOI：
10.1101/gr.261305.120
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发表时间：
2021-12
期刊：
影响因子：
7
通讯作者：
Burns KH
中科院分区：
文献类型：
--
作者：
Payer LM;Steranka JP;Kryatova MS;Grillo G;Lupien M;Rocha PP;Burns KH
Alu是在灵长类动物和人类进化过程中积累在基因附近的高拷贝数穿插重复序列。它们是现代人类结构变异的普遍来源。Alu插入对基因表达的影响尚不清楚，尽管一些与表达数量性状位点（eqtl）有关。在这里，我们直接测试了多态Alu插入在同一单倍型上分离的其他变体的调控作用。为了筛选具有这种影响的插入变异，我们使用异位荧光素酶报告基因检测并评估了110个Alu插入变异，其中包括40多个在疾病风险中具有潜在作用的变异。我们观察到连续的影响与显著异常值，上调或下调荧光素酶活性。使用一系列报告基因结构，其中包括围绕Alu的基因组背景，我们可以区分Alu破坏另一个调控因子的情况和Alu引入新的调控序列的情况。接下来，我们将重点放在与乳腺癌相关的三个多态Alu位点上，它们在报告基因试验中显示出显著的影响。我们使用CRISPR修饰内源性序列，建立了不同Alu基因型的细胞系。我们的研究结果表明，Alu基因型可以改变与癌症风险相关的基因的表达，包括PTHLH、RANBP9和MYC。这些数据表明，常见的多态Alu元素可以改变转录水平，并可能导致疾病风险。
Alu are high copy number interspersed repeats that have accumulated near genes during primate and human evolution. They are a pervasive source of structural variation in modern humans. Impacts that Alu insertions may have on gene expression are not well understood, although some have been associated with expression quantitative trait loci (eQTLs). Here, we directly test regulatory effects of polymorphic Alu insertions in isolation of other variants on the same haplotype. To screen insertion variants for those with such effects, we used ectopic luciferase reporter assays and evaluated 110 Alu insertion variants, including more than 40 with a potential role in disease risk. We observed a continuum of effects with significant outliers that up- or down-regulate luciferase activity. Using a series of reporter constructs, which included genomic context surrounding the Alu, we can distinguish between instances in which the Alu disrupts another regulator and those in which the Alu introduces new regulatory sequence. We next focused on three polymorphic Alu loci associated with breast cancer that display significant effects in the reporter assay. We used CRISPR to modify the endogenous sequences, establishing cell lines varying in the Alu genotype. Our findings indicate that Alu genotype can alter expression of genes implicated in cancer risk, including PTHLH, RANBP9, and MYC. These data show that commonly occurring polymorphic Alu elements can alter transcript levels and potentially contribute to disease risk.
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影响因子：
64.8
作者：
Ernst, Jason;Kheradpour, Pouya;Mikkelsen, Tarjei S.;Shoresh, Noam;Ward, Lucas D.;Epstein, Charles B.;Zhang, Xiaolan;Wang, Li;Issner, Robbyn;Coyne, Michael;Ku, Manching;Durham, Timothy;Kellis, Manolis;Bernstein, Bradley E.
通讯作者：
Bernstein, Bradley E.
影响因子：
7
作者：
Gardner EJ;Lam VK;Harris DN;Chuang NT;Scott EC;Pittard WS;Mills RE;1000 Genomes Project Consortium;Devine SE
通讯作者：
Devine SE
影响因子：
16.6
作者：
Ghoussaini M;Edwards SL;Michailidou K;Nord S;Cowper-Sal Lari R;Desai K;Kar S;Hillman KM;Kaufmann S;Glubb DM;Beesley J;Dennis J;Bolla MK;Wang Q;Dicks E;Guo Q;Schmidt MK;Shah M;Luben R;Brown J;Czene K;Darabi H;Eriksson M;Klevebring D;Bojesen SE;Nordestgaard BG;Nielsen SF;Flyger H;Lambrechts D;Thienpont B;Neven P;Wildiers H;Broeks A;Van't Veer LJ;Th Rutgers EJ;Couch FJ;Olson JE;Hallberg E;Vachon C;Chang-Claude J;Rudolph A;Seibold P;Flesch-Janys D;Peto J;Dos-Santos-Silva I;Gibson L;Nevanlinna H;Muranen TA;Aittomäki K;Blomqvist C;Hall P;Li J;Liu J;Humphreys K;Kang D;Choi JY;Park SK;Noh DY;Matsuo K;Ito H;Iwata H;Yatabe Y;Guénel P;Truong T;Menegaux F;Sanchez M;Burwinkel B;Marme F;Schneeweiss A;Sohn C;Wu AH;Tseng CC;Van Den Berg D;Stram DO;Benitez J;Zamora MP;Perez JI;Menéndez P;Shu XO;Lu W;Gao YT;Cai Q;Cox A;Cross SS;Reed MW;Andrulis IL;Knight JA;Glendon G;Tchatchou S;Sawyer EJ;Tomlinson I;Kerin MJ;Miller N;Haiman CA;Henderson BE;Schumacher F;Le Marchand L;Lindblom A;Margolin S;Teo SH;Yip CH;Lee DS;Wong TY;Hooning MJ;Martens JW;Collée JM;van Deurzen CH;Hopper JL;Southey MC;Tsimiklis H;Kapuscinski MK;Shen CY;Wu PE;Yu JC;Chen ST;Alnæs GG;Borresen-Dale AL;Giles GG;Milne RL;McLean C;Muir K;Lophatananon A;Stewart-Brown S;Siriwanarangsan P;Hartman M;Miao H;Buhari SA;Teo YY;Fasching PA;Haeberle L;Ekici AB;Beckmann MW;Brenner H;Dieffenbach AK;Arndt V;Stegmaier C;Swerdlow A;Ashworth A;Orr N;Schoemaker MJ;García-Closas M;Figueroa J;Chanock SJ;Lissowska J;Simard J;Goldberg MS;Labrèche F;Dumont M;Winqvist R;Pylkäs K;Jukkola-Vuorinen A;Brauch H;Brüning T;Koto YD;Radice P;Peterlongo P;Bonanni B;Volorio S;Dörk T;Bogdanova NV;Helbig S;Mannermaa A;Kataja V;Kosma VM;Hartikainen JM;Devilee P;Tollenaar RA;Seynaeve C;Van Asperen CJ;Jakubowska A;Lubinski J;Jaworska-Bieniek K;Durda K;Slager S;Toland AE;Ambrosone CB;Yannoukakos D;Sangrajrang S;Gaborieau V;Brennan P;McKay J;Hamann U;Torres D;Zheng W;Long J;Anton-Culver H;Neuhausen SL;Luccarini C;Baynes C;Ahmed S;Maranian M;Healey CS;González-Neira A;Pita G;Alonso MR;Alvarez N;Herrero D;Tessier DC;Vincent D;Bacot F;de Santiago I;Carroll J;Caldas C;Brown MA;Lupien M;Kristensen VN;Pharoah PD;Chenevix-Trench G;French JD;Easton DF;Dunning AM;Australian Ovarian Cancer Management Group;Australian Ovarian Cancer Management Group
通讯作者：
Australian Ovarian Cancer Management Group
DOI：
10.1073/pnas.0910668107
发表时间：
2010-05-25
影响因子：
11.1
作者：
Ahmadiyeh, Nasim;Pomerantz, Mark M.;Freedman, Matthew L.
通讯作者：
Freedman, Matthew L.
DOI：
10.1126/science.aad5497
发表时间：
2016-03-04
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Chuong EB;Elde NC;Feschotte C
通讯作者：
Feschotte C