Single nucleus multiomics identifies ZEB1 and MAFB as candidate regulators of Alzheimer's disease-specific cis-regulatory elements.
Single nucleus multiomics identifies ZEB1 and MAFB as candidate regulators of Alzheimer's disease-specific cis-regulatory elements.
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DOI：
10.1016/j.xgen.2023.100263
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发表时间：
2023-03-08
期刊：
影响因子：
--
通讯作者：
Rizzardi, Lindsay F.
中科院分区：
文献类型：
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作者：
Anderson, Ashlyn G.;Rogers, Brianne B.;Loupe, Jacob M.;Rodriguez-Nunez, Ivan;Brazell, J. Nicholas;Roberts, Sydney C.;White, Lauren M.;Bunney, William E.;Bunney, Blynn G.;Watson, Stanley J.;Cochran, J. Nicholas;Myers, Richard M.;Rizzardi, Lindsay F.
来自阿尔茨海默病（AD）供体和未受影响的对照组的脑组织之间的细胞类型特异性转录差异已得到充分证明，但很少有研究严格询问这些改变的调控机制。我们对从7名AD和8名未受影响的供体的皮质组织中分离的105，332个核进行了单核多组学（snRNA-seq + snATAC-seq），以鉴定参与AD相关转录变化的候选顺式调节元件（克雷斯）。我们检测到319，861个基因表达与富含活性克雷斯的细胞类型特异性转座酶可及区域之间的显著相关性或联系。其中，40，831是AD组织特有的。验证实验证实了许多区域的活性，包括APP表达的几个候选调节因子。我们确定ZEB 1和MAFB作为候选转录因子，分别在神经元和小胶质细胞的AD特异性基因调控中发挥重要作用。小胶质细胞链接在AD风险的遗传性和先前确定的活性调控区域方面在全球范围内富集。单核多组学鉴定阿尔茨海默氏症细胞类型特异性调控元件鉴定40，831个阿尔茨海默氏症特异性候选调控元件确认APP表达候选调控因子的增强子样活性提名ZEB 1和MAFB为候选阿尔茨海默氏症特异性反式调控因子将调控元件与特定细胞类型中的靶基因连接可以揭示疾病中破坏的调控机制。在这里，安德森和罗杰斯等人。确定皮质组织中阿尔茨海默氏症特异性元件和调节其活性的候选转录因子。增强子样活性被证明为12个元件，包括几个APP的调节器。
Cell type-specific transcriptional differences between brain tissues from donors with Alzheimer’s disease (AD) and unaffected controls have been well documented, but few studies have rigorously interrogated the regulatory mechanisms responsible for these alterations. We performed single nucleus multiomics (snRNA-seq plus snATAC-seq) on 105,332 nuclei isolated from cortical tissues from 7 AD and 8 unaffected donors to identify candidate cis-regulatory elements (CREs) involved in AD-associated transcriptional changes. We detected 319,861 significant correlations, or links, between gene expression and cell type-specific transposase accessible regions enriched for active CREs. Among these, 40,831 were unique to AD tissues. Validation experiments confirmed the activity of many regions, including several candidate regulators of APP expression. We identified ZEB1 and MAFB as candidate transcription factors playing important roles in AD-specific gene regulation in neurons and microglia, respectively. Microglia links were globally enriched for heritability of AD risk and previously identified active regulatory regions. Single nucleus multiomics to identify cell type-specific regulatory elements in Alzheimer's Identified 40,831 candidate regulatory elements specific to Alzheimer’s Confirmed enhancer-like activity of candidate regulators of APP expression Nominated ZEB1 and MAFB as candidate Alzheimer’s-specific trans-regulators Linking regulatory elements to target genes in specific cell types can reveal regulatory mechanisms disrupted in disease. Here, Anderson and Rogers et al. identify Alzheimer’s-specific elements in cortical tissues and candidate transcription factors regulating their activity. Enhancer-like activity was demonstrated for twelve elements including several regulators of APP.
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影响因子：
30.8
作者：
Bellenguez, Celine;Kucukali, Fahri;Jansen, Iris E.;Kleineidam, Luca;Moreno-Grau, Sonia;Amin, Najaf;Naj, Adam C.;Campos-Martin, Rafael;Grenier-Boley, Benjamin;Andrade, Victor;Holmans, Peter A.;Boland, Anne;Damotte, Vincent;van der Lee, Sven J.;Costa, Marcos R.;Kuulasmaa, Teemu;Yang, Qiong;De Rojas, Itziar;Bis, Joshua C.;Yaqub, Amber;Prokic, Ivana;Chapuis, Julien;Ahmad, Shahzad;Giedraitis, Vilmantas;Aarsland, Dag;Garcia-Gonzalez, Pablo;Abdelnour, Carla;Alarcon-Martin, Emilio;Alcolea, Daniel;Alegret, Montserrat;Alvarez, Ignacio;Alvarez, Victoria;Armstrong, Nicola J.;Tsolaki, Anthoula;Antunez, Carmen;Appollonio, Ildebrando;Arcaro, Marina;Archetti, Silvana;Arias Pastor, Alfonso;Arosio, Beatrice;Athanasiu, Lavinia;Bailly, Henri;Banaj, Nerisa;Baquero, Miquel;Barral, Sandra;Beiser, Alexa;Pastor, Ana Belen;Below, Jennifer E.;Benchek, Penelope;Benussi, Luisa;Berr, Claudine;Besse, Celine;Bessi, Valentina;Binetti, Giuliano;Bizarro, Alessandra;Blesa, Rafael;Boada, Merce;Boerwinkle, Eric;Borroni, Barbara;Boschi, Silvia;Bossu, Paola;Brathen, Geir;Bressler, Jan;Bresner, Catherine;Brodaty, Henry;Brookes, Keeley J.;Ignacio Brusco, Luis;Buiza-Rueda, Dolores;Burger, Katharina;Burholt, Vanessa;Bush, William S.;Calero, Miguel;Cantwell, Laura B.;Chene, Genevieve;Chung, Jaeyoon;Cuccaro, Michael L.;Cecchetti, Roberta;Cervera-Carles, Laura;Charbonnier, Camille;Chen, Hung-Hsin;Chillotti, Caterina;Ciccone, Simona;Claassen, Jurgen A. H. R.;Clark, Christopher;Conti, Elisa;Corma-Gomez, Anais;Costantini, Emanuele;Custodero, Carlo;Daian, Delphine;Dalmasso, Maria Carolina;Daniele, Antonio;Dardiotis, Efthimios;Dartigues, Jean-Francois;de Deyn, Peter Paul;Lopes, Katia de Paiva;De Witte, Lot D.;Debette, Stephanie;Deckert, Jurgen;del Ser, Teodoro;Denning, Nicola;Destefano, Anita;Dichgans, Martin;Diehl-Schmid, Janine;Diez-Fairen, Monica;Rossi, Paolo Dionigi;Djurovic, Srdjan;Duron, Emmanuelle;Duzel, Emrah;Dufouil, Carole;Eiriksdottir, Gudny;Engelborghs, Sebastiaan;Escott-Price, Valentina;Espinosa, Ana;Ewers, Michael;Faber, Kelley M.;Fabrizio, Tagliavini;Nielsen, Sune Fallgaard;Fardo, David W.;Farotti, Lucia;Fenoglio, Chiara;Fernandez-Fuertes, Marta;Ferrari, Raffaele;Ferreira, Catarina B.;Ferri, Evelyn;Fin, Bertrand;Fischer, Peter;Fladby, Tormod;Fliessbach, Klaus;Fongang, Bernard;Fornage, Myriam;Fortea, Juan;Foroud, Tatiana M.;Fostinelli, Silvia;Fox, Nick C.;Franco-Macias, Emlio;Bullido, Maria J.;Frank-Garcia, Ana;Froelich, Lutz;Fulton-Howard, Brian;Galimberti, Daniela;Maria Garcia-Alberca, Jose;Garcia-Madrona, Sebastian;Garcia-Ribas, Guillermo;Ghidoni, Roberta;Giegling, Ina;Giorgio, Giaccone;Goate, Alison M.;Goldhardt, Oliver;Gomez-Fonseca, Duber;Gonzalez-Perez, Antonio;Graff, Caroline;Grande, Giulia;Green, Emma;Grimmer, Timo;Grunblatt, Edna;Grunin, Michelle;Gudnason, Vilmundur;Guetta-Baranes, Tamar;Haapasalo, Annakaisa;Hadjigeorgiou, Georgios;Haines, Jonathan L.;Hamilton-Nelson, Kara L.;Hampel, Harald;Hanon, Olivier;Hardy, John;Hartmann, Annette M.;Hausner, Lucrezia;Harwood, Janet;Heilmann-Heimbach, Stefanie;Helisalmi, Seppo;Heneka, Michael T.;Hernandez, Isabel;Herrmann, Martin J.;Hoffmann, Per;Holmes, Clive;Holstege, Henne;Huerto Vilas, Raquel;Hulsman, Marc;Humphrey, Jack;Biessels, Geert Jan;Jian, Xueqiu;Johansson, Charlotte;Jun, Gyungah R.;Kastumata, Yuriko;Kauwe, John;Kehoe, Patrick G.;Kilander, Lena;Stahlbom, Anne Kinhult;Kivipelto, Miia;Koivisto, Anne;Kornhuber, Johannes;Kosmidis, Mary H.;Kukull, Walter A.;Kuksa, Pavel P.;Kunkle, Brian W.;Kuzma, Amanda B.;Lage, Carmen;Laukka, Erika J.;Launer, Lenore;Lauria, Alessandra;Lee, Chien-Yueh;Lehtisalo, Jenni;Lerch, Ondrej;Lleo, Alberto;Longstreth, William, Jr.;Lopez, Oscar;Lopez de Munain, Adolfo;Love, Seth;Lowemark, Malin;Luckcuck, Lauren;Lunetta, Kathryn L.;Ma, Yiyi;Macias, Juan;Macleod, Catherine A.;Maier, Wolfgang;Mangialasche, Francesca;Spallazzi, Marco;Marquie, Marta;Marshall, Rachel;Martin, Eden R.;Martin Montes, Angel;Martinez Rodriguez, Carmen;Masullo, Carlo;Mayeux, Richard;Mead, Simon;Mecocci, Patrizia;Medina, Miguel;Meggy, Alun;Mehrabian, Shima;Mendoza, Silvia;Menendez-Gonzalez, Manuel;Mir, Pablo;Moebus, Susanne;Mol, Merel;Molina-Porcel, Laura;Montrreal, Laura;Morelli, Laura;Moreno, Fermin;Morgan, Kevin;Mosley, Thomas;Nothen, Markus M.;Muchnik, Carolina;Mukherjee, Shubhabrata;Nacmias, Benedetta;Ngandu, Tiia;Nicolas, Gael;Nordestgaard, Borge G.;Olaso, Robert;Orellana, Adelina;Orsini, Michela;Ortega, Gemma;Padovani, Alessandro;Paolo, Caffarra;Papenberg, Goran;Parnetti, Lucilla;Pasquier, Florence;Pastor, Pau;Peloso, Gina;Perez-Cordon, Alba;Perez-Tur, Jordi;Pericard, Pierre;Peters, Oliver;Pijnenburg, Yolande A. L.;Pineda, Juan A.;Pinol-Ripoll, Gerard;Pisanu, Laudia;Polak, Thomas;Popp, Julius;Posthuma, Danielle;Priller, Josef;Puerta, Raquel;Quenez, Olivier;Quintela, Ines;Thomassen, Jesper Qvist;Rabano, Alberto;Rainero, Innocenzo;Rajabli, Farid;Ramakers, Inez;Real, Luis M.;Reinders, Marcel J. T.;Reitz, Christiane;Reyes-Dumeyer, Dolly;Ridge, Perry;Riedel-Heller, Steffi;Riederer, Peter;Roberto, Natalia;Rodriguez-Rodriguez, Eloy;Rongve, Arvid;Rosas Allende, Irene;Rosende-Roca, Maitee;Luis Royo, Jose;Rubino, Elisa;Rujescu, Dan;Eugenia Saez, Maria;Sakka, Paraskevi;Saltvedt, Ingvild;Bernal Sanchez-Arjona, Maria;Sanchez-Garcia, Florentino;Sanchez Juan, Pascual;Sanchez-Valle, Raquel;Sando, Sigrid B.;Sarnowski, Chloe;Satizabal, Claudia L.;Scamosci, Michela;Scarmeas, Nikolaos;Scarpini, Elio;Scheltens, Philip;Scherbaum, Norbert;Scherer, Martin;Schmid, Matthias;Schneider, Anja;Schott, Jonathan M.;Selbaek, Geir;Seripa, Davide;Serrano, Manuel;Sha, Jin;Shadrin, Alexey A.;Skrobot, Olivia;Slifer, Susan;Snijders, Gijsje J. L.;Soininen, Hilkka;Solfrizzi, Vincenzo;Solomon, Alina;Song, Yeunjoo;Sorbi, Sandro;Sotolongo-Grau, Oscar;Spalletta, Gianfranco;Spottke, Annika;Squassina, Alessio;Stordal, Eystein;Pablo Tartan, Juan;Tarraga, Lluis;Tesi, Niccolo;Thalamuthu, Anbupalam;Thomas, Tegos;Tosto, Giuseppe;Traykov, Latchezar;Tremolizzo, Lucio;Tybjaerg-Hansen, Anne;Uitterlinden, Andre;Ullgren, Abbe;Ulstein, Ingun;Valero, Sergi;Valladares, Otto;Van Broeckhoven, Christine;Vance, Jeffery;Vardarajan, Badri N.;van der Lugt, Aad;Van Dongen, Jasper;van Rooij, Jeroen;van Swieten, John;Vandenberghe, Rik;Verhey, Frans;Vidal, Jean-Sebastien;Vogelgsang, Jonathan;Vyhnalek, Martin;Wagner, Michael;Wallon, David;Wang, Li-San;Wang, Ruiqi;Weinhold, Leonie;Wiltfang, Jens;Windle, Gill;Woods, Bob;Yannakoulia, Mary;Zare, Habil;Zhao, Yi;Zhang, Xiaoling;Zhu, Congcong;Zulaica, Miren;Farrer, Lindsay A.;Psaty, Bruce M.;Ghanbari, Mohsen;Raj, Towfique;Sachdev, Perminder;Mather, Karen;Jessen, Frank;Ikram, M. Arfan;de Mendonca, Alexandre;Hort, Jakub;Tsolaki, Magda;Pericak-Vance, Margaret A.;Amouyel, Philippe;Williams, Julie;Frikke-Schmidt, Ruth;Clarimon, Jordi;Deleuze, Jean-Francois;Rossi, Giacomina;Seshadri, Sudha;Andreassen, Ole A.;Ingelsson, Martin;Hiltunen, Mikko;Sleegers, Kristel;Schellenberg, Gerard D.;van Duijn, Cornelia M.;Sims, Rebecca;van der Flier, Wiesje M.;Ruiz, Agustin;Ramirez, Alfredo;Lambert, Jean-Charles
通讯作者：
Lambert, Jean-Charles
DOI：
10.1038/s41431-021-00866-1
发表时间：
2021-06
期刊：
European journal of human genetics : EJHG
影响因子：
--
作者：
Bourinaris T;Athanasiou A;Efthymiou S;Wiethoff S;Salpietro V;Houlden H
通讯作者：
Houlden H
影响因子：
30.8
作者：
Bulik-Sullivan, Brendan K.;Loh, Po-Ru;Finucane, Hilary K.;Ripke, Stephan;Yang, Jian;Patterson, Nick;Daly, Mark J.;Price, Alkes L.;Neale, Benjamin M.
通讯作者：
Neale, Benjamin M.
影响因子：
30.8
作者：
Finucane HK;Bulik-Sullivan B;Gusev A;Trynka G;Reshef Y;Loh PR;Anttila V;Xu H;Zang C;Farh K;Ripke S;Day FR;ReproGen Consortium;Schizophrenia Working Group of the Psychiatric Genomics Consortium;RACI Consortium;Purcell S;Stahl E;Lindstrom S;Perry JR;Okada Y;Raychaudhuri S;Daly MJ;Patterson N;Neale BM;Price AL
通讯作者：
Price AL
影响因子：
4.8
作者：
通讯作者：
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