Patterns of Gene Expression, Splicing, and Allele-Specific Expression Vary among Macular Tissues and Clinical Stages of Age-Related Macular Degeneration.
Patterns of Gene Expression, Splicing, and Allele-Specific Expression Vary among Macular Tissues and Clinical Stages of Age-Related Macular Degeneration.
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基因表达、剪接和等位基因特异性表达的模式因黄斑组织和年龄相关性黄斑变性的临床阶段而异。
DOI：
10.3390/cells12232668
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发表时间：
2023-11-21
期刊：
影响因子：
6
通讯作者：
DeAngelis, Margaret M.
中科院分区：
文献类型：
--
作者：
Shwani, Treefa;Zhang, Charles;Owen, Leah A.;Shakoor, Akbar;Vitale, Albert T.;Lillvis, John H.;Barr, Julie L.;Cromwell, Parker;Finley, Robert;Husami, Nadine;Au, Elizabeth;Zavala, Rylee A.;Graves, Elijah C.;Zhang, Sarah X.;Farkas, Michael H.;Ammar, David A.;Allison, Karen M.;Tawfik, Amany;Sherva, Richard M.;Li, Mingyao;Stambolian, Dwight;Kim, Ivana K.;Farrer, Lindsay A.;DeAngelis, Margaret M.
关键词：
年龄相关性黄斑变性（AMD）是导致失明的主要原因，阐明其潜在的发病机制对于开发合适的治疗方法至关重要。我们在受疾病影响的组织（黄斑视网膜色素上皮（RPE）/脉络膜以及同一只眼睛内的黄斑神经视网膜）中，确定了AMD临床各阶段的差异表达基因（DEGs）和差异剪接基因（DSGs）。我们按照已发表的标准化方案，使用了来自白种人供体（年龄在60 - 94岁）的27只经过深度表型分析的供体眼睛（在死后6小时内获取）。随后，在另一组特征明确的独立供体眼睛（n = 85）中对重要发现进行了验证。DEGs和DSGs之间的重叠有限，这表明在AMD病理生理学中存在不同的作用机制。与疾病状态之间的DEGs相比，更多先前报道的AMD基因座与DSGs存在重叠，并且在疾病状态之间的黄斑视网膜中未发现DEGs与先前报道的基因座有重叠。此外，我们探究了先前报道的AMD风险基因座编码区域的等位基因特异性表达（ASE），发现在正常眼睛和中期AMD（iAMD）的黄斑RPE/脉络膜中，C3 rs2230199和CFH rs1061170存在显著的表达失衡；在正常眼睛和iAMD以及单独的新生血管性AMD（NEO）的黄斑RPE/脉络膜中，CFH rs1061147也存在表达失衡。仅在疾病状态之间的黄斑RPE/脉络膜中发现了显著的DEGs/DSGs重叠。在iAMD与正常对照的比较中得到验证的STAT1，以及在NEO与正常对照的比较中得到验证的AGTPBP1、BBS5、CERKL、FGFBP2、KIFC3、RORα和ZNF292，揭示了一个复杂的调控网络，其中转录因子和微小RNA（miRNAs）确定了潜在的上游和下游调节因子。关于补体基因C3和CFH的研究结果表明，这些基因座的编码变异可能通过组织特异性的基因表达失衡影响AMD的发展。我们的研究为AMD多方面的基因组基础（即组织特异性基因表达变化、潜在的剪接变异和等位基因失衡）提供了关键见解，这可能为针对iAMD和NEO的AMD诊断和治疗开辟新途径。
Age-related macular degeneration (AMD) is a leading cause of blindness, and elucidating its underlying disease mechanisms is vital to the development of appropriate therapeutics. We identified differentially expressed genes (DEGs) and differentially spliced genes (DSGs) across the clinical stages of AMD in disease-affected tissue, the macular retina pigment epithelium (RPE)/choroid and the macular neural retina within the same eye. We utilized 27 deeply phenotyped donor eyes (recovered within a 6 h postmortem interval time) from Caucasian donors (60–94 years) using a standardized published protocol. Significant findings were then validated in an independent set of well-characterized donor eyes (n = 85). There was limited overlap between DEGs and DSGs, suggesting distinct mechanisms at play in AMD pathophysiology. A greater number of previously reported AMD loci overlapped with DSGs compared to DEGs between disease states, and no DEG overlap with previously reported loci was found in the macular retina between disease states. Additionally, we explored allele-specific expression (ASE) in coding regions of previously reported AMD risk loci, uncovering a significant imbalance in C3 rs2230199 and CFH rs1061170 in the macular RPE/choroid for normal eyes and intermediate AMD (iAMD), and for CFH rs1061147 in the macular RPE/choroid for normal eyes and iAMD, and separately neovascular AMD (NEO). Only significant DEGs/DSGs from the macular RPE/choroid were found to overlap between disease states. STAT1, validated between the iAMD vs. normal comparison, and AGTPBP1, BBS5, CERKL, FGFBP2, KIFC3, RORα, and ZNF292, validated between the NEO vs. normal comparison, revealed an intricate regulatory network with transcription factors and miRNAs identifying potential upstream and downstream regulators. Findings regarding the complement genes C3 and CFH suggest that coding variants at these loci may influence AMD development via an imbalance of gene expression in a tissue-specific manner. Our study provides crucial insights into the multifaceted genomic underpinnings of AMD (i.e., tissue-specific gene expression changes, potential splice variation, and allelic imbalance), which may open new avenues for AMD diagnostics and therapies specific to iAMD and NEO.
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影响因子：
12.3
作者：
Castel SE;Levy-Moonshine A;Mohammadi P;Banks E;Lappalainen T
通讯作者：
Lappalainen T
DOI：
10.7759/cureus.39624
发表时间：
2023-05
期刊：
Cureus
影响因子：
--
作者：
Chaudhuri M;Hassan Y;Bakka Vemana PPS;Bellary Pattanashetty MS;Abdin ZU;Siddiqui HF
通讯作者：
Siddiqui HF
遗传对人体组织基因表达的影响。
影响因子：
64.8
作者：
GTEx Consortium;Laboratory, Data Analysis &Coordinating Center (LDACC)—Analysis Working Group;Statistical Methods groups—Analysis Working Group;Enhancing GTEx (eGTEx) groups;NIH Common Fund;NIH/NCI;NIH/NHGRI;NIH/NIMH;NIH/NIDA;Biospecimen Collection Source Site—NDRI;Biospecimen Collection Source Site—RPCI;Biospecimen Core Resource—VARI;Brain Bank Repository—University of Miami Brain Endowment Bank;Leidos Biomedical—Project Management;ELSI Study;Genome Browser Data Integration &Visualization—EBI;Genome Browser Data Integration &Visualization—UCSC Genomics Institute, University of California Santa Cruz;Lead analysts:;Laboratory, Data Analysis &Coordinating Center (LDACC):;NIH program management:;Biospecimen collection:;Pathology:;eQTL manuscript working group:;Battle A;Brown CD;Engelhardt BE;Montgomery SB
通讯作者：
Montgomery SB
DOI：
10.1038/labinvest.2011.201
发表时间：
2012-05
期刊：
Laboratory investigation; a journal of technical methods and pathology
影响因子：
--
作者：
通讯作者：
--
影响因子：
4.4
作者：
Biasella F;Plössl K;Karl C;Weber BHF;Friedrich U
通讯作者：
Friedrich U