A systems biology approach uncovers novel disease mechanisms in age-related macular degeneration.
A systems biology approach uncovers novel disease mechanisms in age-related macular degeneration.
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DOI：
10.1016/j.xgen.2023.100302
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发表时间：
2023-06-14
期刊：
影响因子：
--
通讯作者：
Deangles, Margaret M.
中科院分区：
文献类型：
--
作者：
Orozco, Luz D.;Owen, Leah A.;Hofmann, Jeffrey;Stockwell, Amy D.;Tao, Jianhua;Haller, Susan;Mukundan, Vineeth T.;Clarke, Christine;Lund, Jessica;Sridhar, Akshayalakshmi;Mayba, Oleg;Barr, Julie L.;Zavala, Rylee A.;Graves, Elijah C.;Zhang, Charles;Husami, Nadine;Finley, Robert;Au, Elizabeth;Lillvis, John H.;Frakas, Michael H.;Shakoor, Akbar;Sherva, Richard;Kim, Ivana K.;Kaminker, Joshua S.;Townsend, Michael J.;Farrer, Lindsay A.;Yaspan, Brian L.;Chen, Hsu-Hsi;Deangles, Margaret M.
老年性黄斑变性(AMD)是导致失明的主要原因，全球有2亿人受到影响。为了确定可以作为治疗靶点的基因，我们在AMD的不同阶段创建了一份分子图谱。我们的资源包括来自临床表型正常和AMD捐赠者眼睛的散装黄斑视网膜色素上皮(RPE)/脉络膜的RNA测序(RNA-SEQ)和DNA甲基化微阵列(n=85)，单核RNA-SEQ(164,399个细胞)，以及来自6个AMD和7个对照组捐赠者的视网膜、RPE和脉络膜的转座酶可及染色质(ATAC)-SEQ(125,822个细胞)的单核分析。我们确定了23个在AMD中差异甲基化的全基因组显著基因，超过1000个在不同疾病阶段的差异表达基因，以及不同于正常或胶质细胞增多症的AMD Müler状态。全基因组关联研究(GWAS)基因座的染色质可及性峰揭示了AMD可能的致病基因，包括HTRA1和C6orf223。我们的系统生物学方法揭示了AMD背后的分子机制，包括WNT信号、FRZB和TLE2的调节，它们是疾病中的机械参与者。表型AMD眼RPE/脉络膜的批量转录组和DNA甲基化来自对照视网膜、RPE和脉络膜的RPE和ATAC-seq以及AMD眼的单核RNA-seq和ATAC-seq优先考虑的可能原因基因在AMD Gwas基因座综合分析确定WNT途径调节因子FRZB和TLE2为AMD基因关于老年性黄斑变性(AMD)的分子变化的有限信息。Orozco等人。在大体组织和单细胞水平上构建对照和表型AMD眼的表达和表观遗传学图谱。他们对这些数据的综合分析揭示了驱动疾病的基因和途径。
Age-related macular degeneration (AMD) is a leading cause of blindness, affecting 200 million people worldwide. To identify genes that could be targeted for treatment, we created a molecular atlas at different stages of AMD. Our resource is comprised of RNA sequencing (RNA-seq) and DNA methylation microarrays from bulk macular retinal pigment epithelium (RPE)/choroid of clinically phenotyped normal and AMD donor eyes (n = 85), single-nucleus RNA-seq (164,399 cells), and single-nucleus assay for transposase-accessible chromatin (ATAC)-seq (125,822 cells) from the retina, RPE, and choroid of 6 AMD and 7 control donors. We identified 23 genome-wide significant loci differentially methylated in AMD, over 1,000 differentially expressed genes across different disease stages, and an AMD Müller state distinct from normal or gliosis. Chromatin accessibility peaks in genome-wide association study (GWAS) loci revealed putative causal genes for AMD, including HTRA1 and C6orf223. Our systems biology approach uncovered molecular mechanisms underlying AMD, including regulators of WNT signaling, FRZB and TLE2, as mechanistic players in disease. Bulk transcriptome and DNA methylation from RPE/choroid of phenotyped AMD eyes Single-nucleus RNA-seq and ATAC-seq from retina, RPE, and choroid of control and AMD eyes Single-nucleus RNA-seq and ATAC-seq prioritized putative causal genes at AMD GWAS loci Integrative analysis identified WNT pathway regulators FRZB and TLE2 as AMD genes There is limited information on molecular changes in age-related macular degeneration (AMD), a leading cause of blindness. Orozco et al. built expression and epigenetic atlases of control and phenotyped AMD eyes at both bulk-tissue and single-cell levels. Their integrative analysis of these data unveiled genes and pathways driving disease.
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影响因子：
16.6
作者：
Cheng, Ching-Yu;Yamashiro, Kenji;Chen, Li Jia;Ahn, Jeeyun;Huang, Lulin;Huang, Lvzhen;Cheung, Chui Ming G.;Miyake, Masahiro;Cackett, Peter D.;Yeo, Ian Y.;Laude, Augustinus;Mathur, Ranjana;Pang, Junxiong;Sim, Kar Seng;Koh, Adrian H.;Chen, Peng;Lee, Shu Yen;Wong, Doric;Chan, Choi Mun;Loh, Boon Kwang;Sun, Yaoyao;Davila, Sonia;Nakata, Isao;Nakanishi, Hideo;Akagi-Kurashige, Yumiko;Gotoh, Norimoto;Tsujikawa, Akitaka;Matsuda, Fumihiko;Mori, Keisuke;Yoneya, Shin;Sakurada, Yoichi;Iijima, Hiroyuki;Iida, Tomohiro;Honda, Shigeru;Lai, Timothy Yuk Yau;Tam, Pancy Oi Sin;Chen, Haoyu;Tang, Shibo;Ding, Xiaoyan;Wen, Feng;Lu, Fang;Zhang, Xiongze;Shi, Yi;Zhao, Peiquan;Zhao, Bowen;Sang, Jinghong;Gong, Bo;Dorajoo, Rajkumar;Yuan, Jian-Min;Koh, Woon-Puay;van Dam, Rob M.;Friedlander, Yechiel;Lin, Ying;Hibberd, Martin L.;Foo, Jia Nee;Wang, Ningli;Wong, Chang Hua;Tan, Gavin S.;Park, Sang Jun;Bhargava, Mayuri;Gopal, Lingam;Naing, Thet;Liao, Jiemin;Ong, Peng Guan;Mitchell, Paul;Zhou, Peng;Xie, Xuefeng;Liang, Jinlong;Mei, Junpu;Jin, Xin;Saw, Seang-Mei;Ozaki, Mineo;Mizoguchi, Takanori;Kurimoto, Yasuo;Woo, Se Joon;Chung, Hum;Yu, Hyeong-Gon;Shin, Joo Young;Park, Dong Ho;Kim, In Taek;Chang, Woohyok;Sagong, Min;Lee, Sang-Joon;Kim, Hyun Woong;Lee, Ji Eun;Li, Yi;Liu, Jianjun;Teo, Yik Ying;Heng, Chew Kiat;Lim, Tock Han;Yang, Suk-Kyun;Song, Kyuyoung;Vithana, Eranga N.;Aung, Tin;Bei, Jin Xin;Zeng, Yi Xin;Tai, E. Shyong;Li, Xiao Xin;Yang, Zhenglin;Park, Kyu-Hyung;Pang, Chi Pui;Yoshimura, Nagahisa;Wong, Tien Yin;Khor, Chiea Chuen
通讯作者：
Khor, Chiea Chuen
影响因子：
64.5
作者：
Cowan CS;Renner M;De Gennaro M;Gross-Scherf B;Goldblum D;Hou Y;Munz M;Rodrigues TM;Krol J;Szikra T;Cuttat R;Waldt A;Papasaikas P;Diggelmann R;Patino-Alvarez CP;Galliker P;Spirig SE;Pavlinic D;Gerber-Hollbach N;Schuierer S;Srdanovic A;Balogh M;Panero R;Kusnyerik A;Szabo A;Stadler MB;Orgül S;Picelli S;Hasler PW;Hierlemann A;Scholl HPN;Roma G;Nigsch F;Roska B
通讯作者：
Roska B
影响因子：
4.4
作者：
An, Eunkyung;Sen, Supti;Hathout, Yetrib
通讯作者：
Hathout, Yetrib
影响因子：
3.5
作者：
Cipriani, Valentina;Leung, Hin-Tak;Yates, John R. W.
通讯作者：
Yates, John R. W.
分泌性卷曲相关蛋白 3 的甲基化和缺失可增强黑色素瘤细胞的迁移和侵袭。
影响因子：
3.7
作者：
Ekström EJ;Sherwood V;Andersson T
通讯作者：
Andersson T