Sex dependent glial-specific changes in the chromatin accessibility landscape in late-onset Alzheimer's disease brains.
Sex dependent glial-specific changes in the chromatin accessibility landscape in late-onset Alzheimer's disease brains.
复制标题
DOI：
10.1186/s13024-021-00481-0
复制
发表时间：
2021-08-24
影响因子：
15.1
通讯作者：
Chiba-Falek O
中科院分区：
文献类型：
--
作者：
Barrera J;Song L;Gamache JE;Garrett ME;Safi A;Yun Y;Premasinghe I;Sprague D;Chipman D;Li J;Fradin H;Soldano K;Gordân R;Ashley-Koch AE;Crawford GE;Chiba-Falek O
在后GWAS时代，破译晚发性阿尔茨海默病(LOAD)的基础遗传病因并将其关联转化为因果关系的需求尚未得到满足。我们使用来自40个冰冻脑组织的Neun分类核进行ATAC-SEQ分析，以细胞类型特定的方式确定染色质可及性景观中负载特定的变化。我们在神经元核中发现了211个负载特异性差异染色质可及性位点，其中4个与负载-GWA区重叠(±100 kb的单核苷酸多态)。虽然非神经元核团没有表现出负荷特异性的差异，但按性别分层在女性中确定了842个负荷特异性染色质可及性点。在非神经元样本中，有7个性别相关的位置与包括APOE在内的Load-Gwas区域重叠。使用单核RNA-SEQ数据集从功能上验证了负载基因座。使用大脑分类核能够识别染色质结构中性别相关的细胞类型特定负载变化。这些发现加强了对LOAD-GWAs发现的解释，提供了潜在的致病机制，并提出了新的LOAD-Location。网上版载有补充材料，可在10.1186/s13024-021-00481-0查阅。
In the post-GWAS era, there is an unmet need to decode the underpinning genetic etiologies of late-onset Alzheimer’s disease (LOAD) and translate the associations to causation. We conducted ATAC-seq profiling using NeuN sorted-nuclei from 40 frozen brain tissues to determine LOAD-specific changes in chromatin accessibility landscape in a cell-type specific manner. We identified 211 LOAD-specific differential chromatin accessibility sites in neuronal-nuclei, four of which overlapped with LOAD-GWAS regions (±100 kb of SNP). While the non-neuronal nuclei did not show LOAD-specific differences, stratification by sex identified 842 LOAD-specific chromatin accessibility sites in females. Seven of these sex-dependent sites in the non-neuronal samples overlapped LOAD-GWAS regions including APOE. LOAD loci were functionally validated using single-nuclei RNA-seq datasets. Using brain sorted-nuclei enabled the identification of sex-dependent cell type-specific LOAD alterations in chromatin structure. These findings enhance the interpretation of LOAD-GWAS discoveries, provide potential pathomechanisms, and suggest novel LOAD-loci. The online version contains supplementary material available at 10.1186/s13024-021-00481-0.
登录
查看更多内容
影响因子：
30.8
作者：
Harold, Denise;Abraham, Richard;Hollingworth, Paul;Sims, Rebecca;Gerrish, Amy;Hamshere, Marian L.;Pahwa, Jaspreet Singh;Moskvina, Valentina;Dowzell, Kimberley;Williams, Amy;Jones, Nicola;Thomas, Charlene;Stretton, Alexandra;Morgan, Angharad R.;Lovestone, Simon;Powell, John;Proitsi, Petroula;Lupton, Michelle K.;Brayne, Carol;Rubinsztein, David C.;Gill, Michael;Lawlor, Brian;Lynch, Aoibhinn;Morgan, Kevin;Brown, Kristelle S.;Passmore, Peter A.;Craig, David;McGuinness, Bernadette;Todd, Stephen;Holmes, Clive;Mann, David;Smith, A. David;Love, Seth;Kehoe, Patrick G.;Hardy, John;Mead, Simon;Fox, Nick;Rossor, Martin;Collinge, John;Maier, Wolfgang;Jessen, Frank;Schuermann, Britta;van den Bussche, Hendrik;Heuser, Isabella;Kornhuber, Johannes;Wiltfang, Jens;Dichgans, Martin;Froelich, Lutz;Hampel, Harald;Huell, Michael;Rujescu, Dan;Goate, Alison M.;Kauwe, John S. K.;Cruchaga, Carlos;Nowotny, Petra;Morris, John C.;Mayo, Kevin;Sleegers, Kristel;Bettens, Karolien;Engelborghs, Sebastiaan;De Deyn, Peter P.;Van Broeckhoven, Christine;Livingston, Gill;Bass, Nicholas J.;Gurling, Hugh;McQuillin, Andrew;Gwilliam, Rhian;Deloukas, Panagiotis;Al-Chalabi, Ammar;Shaw, Christopher E.;Tsolaki, Magda;Singleton, Andrew B.;Guerreiro, Rita;Muehleisen, Thomas W.;Noethen, Markus M.;Moebus, Susanne;Joeckel, Karl-Heinz;Klopp, Norman;Wichmann, H-Erich;Carrasquillo, Minerva M.;Pankratz, V. Shane;Younkin, Steven G.;Holmans, Peter A.;O'Donovan, Michael;Owen, Michael J.;Williams, Julie
通讯作者：
Williams, Julie
影响因子：
2.1
作者：
Bretsky, PM;Buckwalter, JG;Henderson, VW
通讯作者：
Henderson, VW
影响因子：
7.7
作者：
Harrington, Adam J.;Raissi, Aram;Cowan, Christopher W.
通讯作者：
Cowan, Christopher W.
影响因子：
14.9
作者：
Bailey TL;Johnson J;Grant CE;Noble WS
通讯作者：
Noble WS
影响因子：
16
作者：
Heinz S;Benner C;Spann N;Bertolino E;Lin YC;Laslo P;Cheng JX;Murre C;Singh H;Glass CK
通讯作者：
Glass CK