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Prevention of acquired sensorineural hearing loss in mice by in vivo Htra2 gene editing. 通过体内 Htra2 基因编辑预防小鼠获得性感音神经性听力损失。
IF 12.3 1区 生物学 Q1 Agricultural and Biological Sciences Pub Date : 2021-03-22 DOI: 10.1186/s13059-021-02311-4
Xi Gu, Daqi Wang, Zhijiao Xu, Jinghan Wang, Luo Guo, Renjie Chai, Genglin Li, Yilai Shu, Huawei Li

Background: Aging, noise, infection, and ototoxic drugs are the major causes of human acquired sensorineural hearing loss, but treatment options are limited. CRISPR/Cas9 technology has tremendous potential to become a new therapeutic modality for acquired non-inherited sensorineural hearing loss. Here, we develop CRISPR/Cas9 strategies to prevent aminoglycoside-induced deafness, a common type of acquired non-inherited sensorineural hearing loss, via disrupting the Htra2 gene in the inner ear which is involved in apoptosis but has not been investigated in cochlear hair cell protection.

Results: The results indicate that adeno-associated virus (AAV)-mediated delivery of CRISPR/SpCas9 system ameliorates neomycin-induced apoptosis, promotes hair cell survival, and significantly improves hearing function in neomycin-treated mice. The protective effect of the AAV-CRISPR/Cas9 system in vivo is sustained up to 8 weeks after neomycin exposure. For more efficient delivery of the whole CRISPR/Cas9 system, we also explore the AAV-CRISPR/SaCas9 system to prevent neomycin-induced deafness. The in vivo editing efficiency of the SaCas9 system is 1.73% on average. We observed significant improvement in auditory brainstem response thresholds in the injected ears compared with the non-injected ears. At 4 weeks after neomycin exposure, the protective effect of the AAV-CRISPR/SaCas9 system is still obvious, with the improvement in auditory brainstem response threshold up to 50 dB at 8 kHz.

Conclusions: These findings demonstrate the safe and effective prevention of aminoglycoside-induced deafness via Htra2 gene editing and support further development of the CRISPR/Cas9 technology in the treatment of non-inherited hearing loss as well as other non-inherited diseases.

背景:衰老、噪音、感染和耳毒性药物是导致人类获得性感音神经性听力损失的主要原因,但治疗方法却很有限。CRISPR/Cas9技术具有巨大潜力,可成为治疗后天性非遗传性感音神经性听力损失的新方法。在此,我们开发了CRISPR/Cas9策略,通过破坏内耳中参与细胞凋亡但尚未在耳蜗毛细胞保护中进行研究的Htra2基因来预防氨基糖苷类药物诱发的耳聋(一种常见的后天性非遗传性感音神经性听力损失):结果表明,腺相关病毒(AAV)介导的 CRISPR/SpCas9 系统能改善新霉素诱导的细胞凋亡,促进毛细胞存活,并显著改善新霉素治疗小鼠的听力功能。AAV-CRISPR/Cas9 系统在体内的保护作用在新霉素暴露后可持续 8 周。为了更有效地传递整个 CRISPR/Cas9 系统,我们还探索了 AAV-CRISPR/SaCas9 系统来预防新霉素诱导的耳聋。SaCas9 系统的体内编辑效率平均为 1.73%。与未注射的耳朵相比,我们观察到注射耳朵的听觉脑干反应阈值有明显改善。在暴露于新霉素4周后,AAV-CRISPR/SaCas9系统的保护作用仍然明显,在8 kHz时听性脑干反应阈值的改善达50 dB:这些研究结果表明,通过 Htra2 基因编辑可以安全有效地预防氨基糖苷类药物诱发的耳聋,并支持 CRISPR/Cas9 技术在治疗非遗传性听力损失以及其他非遗传性疾病方面的进一步发展。
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引用次数: 0
Histone lactylation drives oncogenesis by facilitating m6A reader protein YTHDF2 expression in ocular melanoma. 组蛋白乳酸化通过促进m6A读取器蛋白YTHDF2在眼部黑色素瘤中的表达来驱动肿瘤发生。
IF 12.3 1区 生物学 Q1 Agricultural and Biological Sciences Pub Date : 2021-03-16 DOI: 10.1186/s13059-021-02308-z
Jie Yu, Peiwei Chai, Minyue Xie, Shengfang Ge, Jing Ruan, Xianqun Fan, Renbing Jia

Background: Histone lactylation, a metabolic stress-related histone modification, plays an important role in the regulation of gene expression during M1 macrophage polarization. However, the role of histone lactylation in tumorigenesis remains unclear.

Results: Here, we show histone lactylation is elevated in tumors and is associated with poor prognosis of ocular melanoma. Target correction of aberrant histone lactylation triggers therapeutic efficacy both in vitro and in vivo. Mechanistically, histone lactylation contributes to tumorigenesis by facilitating YTHDF2 expression. Moreover, YTHDF2 recognizes the m6A modified PER1 and TP53 mRNAs and promotes their degradation, which accelerates tumorigenesis of ocular melanoma.

Conclusion: We reveal the oncogenic role of histone lactylation, thereby providing novel therapeutic targets for ocular melanoma therapy. We also bridge histone modifications with RNA modifications, which provides novel understanding of epigenetic regulation in tumorigenesis.

背景:组蛋白乳酸化是一种与代谢应激相关的组蛋白修饰,在M1巨噬细胞极化过程中对基因表达的调控中起着重要作用。然而,组蛋白乳酸化在肿瘤发生中的作用尚不清楚。结果:在这里,我们发现组蛋白乳酸化在肿瘤中升高,并与眼部黑色素瘤的不良预后有关。靶校正异常组蛋白乳酸化触发治疗效果在体外和体内。从机制上讲,组蛋白乳酸化通过促进YTHDF2的表达而促进肿瘤发生。此外,YTHDF2识别m6A修饰的PER1和TP53 mrna并促进其降解,从而加速眼部黑色素瘤的发生。结论:我们揭示了组蛋白乳酸化的致瘤作用,从而为眼部黑色素瘤的治疗提供了新的治疗靶点。我们还在组蛋白修饰和RNA修饰之间架起了桥梁,这为肿瘤发生中的表观遗传调控提供了新的理解。
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引用次数: 1
Prime editing in mice reveals the essentiality of a single base in driving tissue-specific gene expression. 小鼠的主碱基编辑揭示了单个碱基在驱动组织特异性基因表达中的重要性。
IF 12.3 1区 生物学 Q1 Agricultural and Biological Sciences Pub Date : 2021-03-16 DOI: 10.1186/s13059-021-02304-3
Pan Gao, Qing Lyu, Amr R Ghanam, Cicera R Lazzarotto, Gregory A Newby, Wei Zhang, Mihyun Choi, Orazio J Slivano, Kevin Holden, John A Walker, Anastasia P Kadina, Rob J Munroe, Christian M Abratte, John C Schimenti, David R Liu, Shengdar Q Tsai, Xiaochun Long, Joseph M Miano

Background: Most single nucleotide variants (SNVs) occur in noncoding sequence where millions of transcription factor binding sites (TFBS) reside. Here, a comparative analysis of CRISPR-mediated homology-directed repair (HDR) versus the recently reported prime editing 2 (PE2) system was carried out in mice over a TFBS called a CArG box in the Tspan2 promoter.

Results: Quantitative RT-PCR showed loss of Tspan2 mRNA in aorta and bladder, but not heart or brain, of mice homozygous for an HDR-mediated three base pair substitution in the Tspan2 CArG box. Using the same protospacer, mice homozygous for a PE2-mediated single-base substitution in the Tspan2 CArG box displayed similar cell-specific loss of Tspan2 mRNA; expression of an overlapping long noncoding RNA was also nearly abolished in aorta and bladder. Immuno-RNA fluorescence in situ hybridization validated loss of Tspan2 in vascular smooth muscle cells of HDR and PE2 CArG box mutant mice. Targeted sequencing demonstrated variable frequencies of on-target editing in all PE2 and HDR founders. However, whereas no on-target indels were detected in any of the PE2 founders, all HDR founders showed varying levels of on-target indels. Off-target analysis by targeted sequencing revealed mutations in many HDR founders, but none in PE2 founders.

Conclusions: PE2 directs high-fidelity editing of a single base in a TFBS leading to cell-specific loss in expression of an mRNA/long noncoding RNA gene pair. The PE2 platform expands the genome editing toolbox for modeling and correcting relevant noncoding SNVs in the mouse.

背景:大多数单核苷酸变异(SNV)发生在非编码序列中,而这些序列中存在数百万个转录因子结合位点(TFBS)。在此,我们对 CRISPR 介导的同源定向修复(HDR)与最近报道的质粒编辑 2(PE2)系统进行了比较分析:结果:定量 RT-PCR 显示,在 Tspan2 CArG 框中由 HDR 介导的三个碱基对置换的同源小鼠中,主动脉和膀胱中的 Tspan2 mRNA 丢失,但心脏和大脑中的 Tspan2 mRNA 没有丢失。使用相同的原间隔子,Tspan2 CArG 框中 PE2 介导的单碱基替换的同源小鼠也表现出类似的细胞特异性 Tspan2 mRNA 缺失;在主动脉和膀胱中,重叠的长非编码 RNA 的表达也几乎消失。免疫 RNA 荧光原位杂交验证了 HDR 和 PE2 CArG 盒突变小鼠血管平滑肌细胞中 Tspan2 的缺失。靶向测序显示,在所有 PE2 和 HDR 基因中,靶上编辑的频率各不相同。然而,虽然在所有 PE2 基因中都没有检测到靶上嵌合体,但在所有 HDR 基因中都出现了不同程度的靶上嵌合体。通过靶向测序进行的脱靶分析在许多 HDR 基因发现了突变,但在 PE2 基因中没有发现突变:结论:PE2 可对 TFBS 中的一个碱基进行高保真编辑,导致 mRNA/长非编码 RNA 基因对的细胞特异性表达缺失。PE2 平台扩展了基因组编辑工具箱,可用于建模和校正小鼠的相关非编码 SNV。
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引用次数: 0
Kssd: sequence dimensionality reduction by k-mer substring space sampling enables real-time large-scale datasets analysis. Kssd:通过 k-mer 子串空间采样降低序列维度,实现实时大规模数据集分析。
IF 12.3 1区 生物学 Q1 Agricultural and Biological Sciences Pub Date : 2021-03-16 DOI: 10.1186/s13059-021-02303-4
Huiguang Yi, Yanling Lin, Chengqi Lin, Wenfei Jin

Here, we develop k -mer substring space decomposition (Kssd), a sketching technique which is significantly faster and more accurate than current sketching methods. We show that it is the only method that can be used for large-scale dataset comparisons at population resolution on simulated and real data. Using Kssd, we prioritize references for all 1,019,179 bacteria whole genome sequencing (WGS) runs from NCBI Sequence Read Archive and find misidentification or contamination in 6164 of these. Additionally, we analyze WGS and exome runs of samples from the 1000 Genomes Project.

在这里,我们开发了 k -mer 子串空间分解(Kssd),这是一种草图绘制技术,与当前的草图绘制方法相比,速度更快,精度更高。我们的研究表明,这是唯一一种可以在模拟数据和真实数据的群体分辨率下进行大规模数据集比较的方法。利用 Kssd,我们对 NCBI Sequence Read Archive 中所有 1,019,179 个细菌全基因组测序(WGS)运行的参考文献进行了优先排序,发现其中 6164 个存在识别错误或污染。此外,我们还分析了来自 1000 基因组计划的 WGS 和外显子组运行样本。
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引用次数: 0
SRSF3 and SRSF7 modulate 3'UTR length through suppression or activation of proximal polyadenylation sites and regulation of CFIm levels. SRSF3和SRSF7通过抑制或激活近端聚腺苷化位点和调节CFIm水平来调节3'UTR长度。
IF 12.3 1区 生物学 Q1 Agricultural and Biological Sciences Pub Date : 2021-03-11 DOI: 10.1186/s13059-021-02298-y
Oliver Daniel Schwich, Nicole Blümel, Mario Keller, Marius Wegener, Samarth Thonta Setty, Melinda Elaine Brunstein, Ina Poser, Igor Ruiz De Los Mozos, Beatrix Suess, Christian Münch, François McNicoll, Kathi Zarnack, Michaela Müller-McNicoll

Background: Alternative polyadenylation (APA) refers to the regulated selection of polyadenylation sites (PASs) in transcripts, which determines the length of their 3' untranslated regions (3'UTRs). We have recently shown that SRSF3 and SRSF7, two closely related SR proteins, connect APA with mRNA export. The mechanism underlying APA regulation by SRSF3 and SRSF7 remained unknown.

Results: Here we combine iCLIP and 3'-end sequencing and find that SRSF3 and SRSF7 bind upstream of proximal PASs (pPASs), but they exert opposite effects on 3'UTR length. SRSF7 enhances pPAS usage in a concentration-dependent but splicing-independent manner by recruiting the cleavage factor FIP1, generating short 3'UTRs. Protein domains unique to SRSF7, which are absent from SRSF3, contribute to FIP1 recruitment. In contrast, SRSF3 promotes distal PAS (dPAS) usage and hence long 3'UTRs directly by counteracting SRSF7, but also indirectly by maintaining high levels of cleavage factor Im (CFIm) via alternative splicing. Upon SRSF3 depletion, CFIm levels decrease and 3'UTRs are shortened. The indirect SRSF3 targets are particularly sensitive to low CFIm levels, because here CFIm serves a dual function; it enhances dPAS and inhibits pPAS usage by binding immediately downstream and assembling unproductive cleavage complexes, which together promotes long 3'UTRs.

Conclusions: We demonstrate that SRSF3 and SRSF7 are direct modulators of pPAS usage and show how small differences in the domain architecture of SR proteins can confer opposite effects on pPAS regulation.

背景:选择性聚腺苷化(APA)是指转录本中聚腺苷化位点(PASs)的调控选择,它决定了转录本3'非翻译区(3' utr)的长度。我们最近发现,两个密切相关的SR蛋白SRSF3和SRSF7将APA与mRNA的输出联系起来。SRSF3和SRSF7调控APA的机制尚不清楚。结果:本研究结合iCLIP和3’端测序发现,SRSF3和SRSF7结合在近端PASs (pPASs)上游,但对3’utr长度的影响相反。SRSF7通过招募裂解因子FIP1,产生短的3' utr,以浓度依赖但与剪接无关的方式增强了pPAS的使用。SRSF7特有的蛋白结构域参与了FIP1的募集,而SRSF3中没有。相反,SRSF3通过抵消SRSF7直接促进远端PAS (dPAS)的使用,从而促进长3' utr,但也通过选择性剪接间接维持高水平的切割因子Im (CFIm)。SRSF3耗竭后,CFIm水平降低,3' utr缩短。间接的SRSF3靶点对低CFIm水平特别敏感,因为CFIm在这里具有双重功能;它通过直接结合下游和组装非生产性裂解复合物来增强dPAS并抑制pPAS的使用,这些裂解复合物共同促进长3' utr。结论:我们证明SRSF3和SRSF7是pPAS使用的直接调节剂,并表明SR蛋白结构域结构的微小差异如何对pPAS调节产生相反的影响。
{"title":"SRSF3 and SRSF7 modulate 3'UTR length through suppression or activation of proximal polyadenylation sites and regulation of CFIm levels.","authors":"Oliver Daniel Schwich,&nbsp;Nicole Blümel,&nbsp;Mario Keller,&nbsp;Marius Wegener,&nbsp;Samarth Thonta Setty,&nbsp;Melinda Elaine Brunstein,&nbsp;Ina Poser,&nbsp;Igor Ruiz De Los Mozos,&nbsp;Beatrix Suess,&nbsp;Christian Münch,&nbsp;François McNicoll,&nbsp;Kathi Zarnack,&nbsp;Michaela Müller-McNicoll","doi":"10.1186/s13059-021-02298-y","DOIUrl":"https://doi.org/10.1186/s13059-021-02298-y","url":null,"abstract":"<p><strong>Background: </strong>Alternative polyadenylation (APA) refers to the regulated selection of polyadenylation sites (PASs) in transcripts, which determines the length of their 3' untranslated regions (3'UTRs). We have recently shown that SRSF3 and SRSF7, two closely related SR proteins, connect APA with mRNA export. The mechanism underlying APA regulation by SRSF3 and SRSF7 remained unknown.</p><p><strong>Results: </strong>Here we combine iCLIP and 3'-end sequencing and find that SRSF3 and SRSF7 bind upstream of proximal PASs (pPASs), but they exert opposite effects on 3'UTR length. SRSF7 enhances pPAS usage in a concentration-dependent but splicing-independent manner by recruiting the cleavage factor FIP1, generating short 3'UTRs. Protein domains unique to SRSF7, which are absent from SRSF3, contribute to FIP1 recruitment. In contrast, SRSF3 promotes distal PAS (dPAS) usage and hence long 3'UTRs directly by counteracting SRSF7, but also indirectly by maintaining high levels of cleavage factor Im (CFIm) via alternative splicing. Upon SRSF3 depletion, CFIm levels decrease and 3'UTRs are shortened. The indirect SRSF3 targets are particularly sensitive to low CFIm levels, because here CFIm serves a dual function; it enhances dPAS and inhibits pPAS usage by binding immediately downstream and assembling unproductive cleavage complexes, which together promotes long 3'UTRs.</p><p><strong>Conclusions: </strong>We demonstrate that SRSF3 and SRSF7 are direct modulators of pPAS usage and show how small differences in the domain architecture of SR proteins can confer opposite effects on pPAS regulation.</p>","PeriodicalId":48922,"journal":{"name":"Genome Biology","volume":"22 1","pages":"82"},"PeriodicalIF":12.3,"publicationDate":"2021-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1186/s13059-021-02298-y","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"25466202","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 26
gapseq: informed prediction of bacterial metabolic pathways and reconstruction of accurate metabolic models. gapseq:细菌代谢途径的知情预测和准确代谢模型的重建。
IF 12.3 1区 生物学 Q1 Agricultural and Biological Sciences Pub Date : 2021-03-10 DOI: 10.1186/s13059-021-02295-1
Johannes Zimmermann, Christoph Kaleta, Silvio Waschina

Genome-scale metabolic models of microorganisms are powerful frameworks to predict phenotypes from an organism's genotype. While manual reconstructions are laborious, automated reconstructions often fail to recapitulate known metabolic processes. Here we present gapseq ( https://github.com/jotech/gapseq ), a new tool to predict metabolic pathways and automatically reconstruct microbial metabolic models using a curated reaction database and a novel gap-filling algorithm. On the basis of scientific literature and experimental data for 14,931 bacterial phenotypes, we demonstrate that gapseq outperforms state-of-the-art tools in predicting enzyme activity, carbon source utilisation, fermentation products, and metabolic interactions within microbial communities.

微生物的基因组尺度代谢模型是根据生物基因型预测表型的强大框架。人工重建费时费力,而自动重建往往不能再现已知的代谢过程。在这里,我们介绍一种新的工具 gapseq ( https://github.com/jotech/gapseq ) ,它可以预测代谢途径,并利用一个经过整理的反应数据库和一种新颖的填补空白算法自动重建微生物代谢模型。根据科学文献和 14931 种细菌表型的实验数据,我们证明了 gapseq 在预测微生物群落中的酶活性、碳源利用、发酵产物和代谢相互作用方面优于最先进的工具。
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引用次数: 0
Identification of pathogenic variants in cancer genes using base editing screens with editing efficiency correction. 利用具有编辑效率校正功能的碱基编辑筛选确定癌症基因中的致病变异。
IF 12.3 1区 生物学 Q1 Agricultural and Biological Sciences Pub Date : 2021-03-10 DOI: 10.1186/s13059-021-02305-2
Changcai Huang, Guangyu Li, Jiayu Wu, Junbo Liang, Xiaoyue Wang

Background: Millions of nucleotide variants are identified through cancer genome sequencing and it is clinically important to identify the pathogenic variants among them. By introducing base substitutions at guide RNA target regions in the genome, CRISPR-Cas9-based base editors provide the possibility for evaluating a large number of variants in their genomic context. However, the variability in editing efficiency and the complexity of outcome mapping are two existing problems for assigning guide RNA effects to variants in base editing screens.

Results: To improve the identification of pathogenic variants, we develop a framework to combine base editing screens with sgRNA efficiency and outcome mapping. We apply the method to evaluate more than 9000 variants across all the exons of BRCA1 and BRCA2 genes. Our efficiency-corrected scoring model identifies 910 loss-of-function variants for BRCA1/2, including 151 variants in the noncoding part of the genes such as the 5' untranslated regions. Many of them are identified in cancer patients and are reported as "benign/likely benign" or "variants of uncertain significance" by clinicians. Our data suggest a need to re-evaluate their clinical significance, which may be helpful for risk assessment and treatment of breast and ovarian cancer.

Conclusions: Our results suggest that base editing screens with efficiency correction is a powerful strategy to identify pathogenic variants in a high-throughput manner. Applying this strategy to assess variants in both coding and noncoding regions of the genome could have a direct impact on the interpretation of cancer variants.

背景:通过癌症基因组测序确定了数百万个核苷酸变异,而确定其中的致病变异具有重要的临床意义。基于 CRISPR-Cas9 的碱基编辑器通过在基因组中的引导 RNA 靶区引入碱基替换,为评估基因组上下文中的大量变异提供了可能。然而,编辑效率的可变性和结果图谱的复杂性是目前在碱基编辑筛选中将向导 RNA 的效应分配给变异体的两个问题:为了更好地识别致病变异,我们开发了一个框架,将碱基编辑筛选与 sgRNA 效率和结果图谱相结合。我们应用该方法评估了 BRCA1 和 BRCA2 基因所有外显子中的 9000 多个变异。我们的效率校正评分模型确定了 BRCA1/2 的 910 个功能缺失变异,包括基因非编码部分(如 5' 非翻译区)的 151 个变异。其中许多变异是在癌症患者中发现的,临床医生将其报告为 "良性/可能良性 "或 "意义不确定的变异"。我们的数据表明,有必要重新评估它们的临床意义,这可能有助于乳腺癌和卵巢癌的风险评估和治疗:我们的研究结果表明,带有效率校正的碱基编辑筛选是一种以高通量方式鉴定致病变异的强大策略。应用这种策略评估基因组编码区和非编码区的变异可能会对癌症变异的解释产生直接影响。
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引用次数: 0
Genetic variation and microRNA targeting of A-to-I RNA editing fine tune human tissue transcriptomes. 遗传变异和微RNA靶向A-to-I RNA编辑微调人体组织转录组。
IF 12.3 1区 生物学 Q1 Agricultural and Biological Sciences Pub Date : 2021-03-09 DOI: 10.1186/s13059-021-02287-1
Eddie Park, Yan Jiang, Lili Hao, Jingyi Hui, Yi Xing

Background: A-to-I RNA editing diversifies the transcriptome and has multiple downstream functional effects. Genetic variation contributes to RNA editing variability between individuals and has the potential to impact phenotypic variability.

Results: We analyze matched genetic and transcriptomic data in 49 tissues across 437 individuals to identify RNA editing events that are associated with genetic variation. Using an RNA editing quantitative trait loci (edQTL) mapping approach, we identify 3117 unique RNA editing events associated with a cis genetic polymorphism. Fourteen percent of these edQTL events are also associated with genetic variation in their gene expression. A subset of these events are associated with genome-wide association study signals of complex traits or diseases. We determine that tissue-specific levels of ADAR and ADARB1 are able to explain a subset of tissue-specific edQTL events. We find that certain microRNAs are able to differentiate between the edited and unedited isoforms of their targets. Furthermore, microRNAs can generate an expression quantitative trait loci (eQTL) signal from an edQTL locus by microRNA-mediated transcript degradation in an editing-specific manner. By integrative analyses of edQTL, eQTL, and microRNA expression profiles, we computationally discover and experimentally validate edQTL-microRNA pairs for which the microRNA may generate an eQTL signal from an edQTL locus in a tissue-specific manner.

Conclusions: Our work suggests a mechanism in which RNA editing variability can influence the phenotypes of complex traits and diseases by altering the stability and steady-state level of critical RNA molecules.

背景:A 到 I RNA 编辑使转录组多样化,并具有多种下游功能效应。遗传变异导致个体间 RNA 编辑的变异,并有可能影响表型的变异:我们分析了 437 个个体 49 种组织中匹配的遗传和转录组数据,以确定与遗传变异相关的 RNA 编辑事件。利用RNA编辑定量性状位点(edQTL)绘图方法,我们确定了3117个与顺式遗传多态性相关的独特RNA编辑事件。其中 14% 的 edQTL 事件还与基因表达的遗传变异有关。这些事件的一部分与复杂性状或疾病的全基因组关联研究信号有关。我们确定,组织特异性水平的 ADAR 和 ADARB1 能够解释一部分组织特异性 edQTL 事件。我们发现,某些 microRNA 能够区分其靶标的编辑异构体和未编辑异构体。此外,microRNA还能以编辑特异性的方式,通过microRNA介导的转录本降解,从edQTL位点产生表达定量性状位点(eQTL)信号。通过对edQTL、eQTL和microRNA表达谱的综合分析,我们通过计算发现并通过实验验证了edQTL-microRNA对,其中microRNA可能以组织特异性的方式从edQTL基因座产生eQTL信号:我们的工作提出了一种机制,即 RNA 编辑变异可通过改变关键 RNA 分子的稳定性和稳态水平来影响复杂性状和疾病的表型。
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引用次数: 0
riboCIRC: a comprehensive database of translatable circRNAs. riboCIRC:可翻译 circRNAs 的综合数据库。
IF 12.3 1区 生物学 Q1 Agricultural and Biological Sciences Pub Date : 2021-03-08 DOI: 10.1186/s13059-021-02300-7
Huihui Li, Mingzhe Xie, Yan Wang, Ludong Yang, Zhi Xie, Hongwei Wang

riboCIRC is a translatome data-oriented circRNA database specifically designed for hosting, exploring, analyzing, and visualizing translatable circRNAs from multi-species. The database provides a comprehensive repository of computationally predicted ribosome-associated circRNAs; a manually curated collection of experimentally verified translated circRNAs; an evaluation of cross-species conservation of translatable circRNAs; a systematic de novo annotation of putative circRNA-encoded peptides, including sequence, structure, and function; and a genome browser to visualize the context-specific occupant footprints of circRNAs. It represents a valuable resource for the circRNA research community and is publicly available at http://www.ribocirc.com .

riboCIRC 是一个以翻译组数据为导向的 circRNA 数据库,专门用于托管、探索、分析和可视化来自多物种的可翻译 circRNA。该数据库提供了一个计算预测的核糖体相关 circRNAs 的综合资料库;一个人工编辑的经实验验证的翻译 circRNAs 库;对可翻译 circRNAs 的跨物种保护进行评估;对推测的 circRNA 编码肽进行系统的从头注释,包括序列、结构和功能;以及一个基因组浏览器,用于可视化 circRNAs 在特定环境中的占位足迹。它是 circRNA 研究界的宝贵资源,可通过 http://www.ribocirc.com 公开获取。
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引用次数: 0
Giotto: a toolbox for integrative analysis and visualization of spatial expression data. 空间表达数据的综合分析和可视化工具箱。
IF 12.3 1区 生物学 Q1 Agricultural and Biological Sciences Pub Date : 2021-03-08 DOI: 10.1186/s13059-021-02286-2
Ruben Dries, Qian Zhu, Rui Dong, Chee-Huat Linus Eng, Huipeng Li, Kan Liu, Yuntian Fu, Tianxiao Zhao, Arpan Sarkar, Feng Bao, Rani E George, Nico Pierson, Long Cai, Guo-Cheng Yuan

Spatial transcriptomic and proteomic technologies have provided new opportunities to investigate cells in their native microenvironment. Here we present Giotto, a comprehensive and open-source toolbox for spatial data analysis and visualization. The analysis module provides end-to-end analysis by implementing a wide range of algorithms for characterizing tissue composition, spatial expression patterns, and cellular interactions. Furthermore, single-cell RNAseq data can be integrated for spatial cell-type enrichment analysis. The visualization module allows users to interactively visualize analysis outputs and imaging features. To demonstrate its general applicability, we apply Giotto to a wide range of datasets encompassing diverse technologies and platforms.

空间转录组学和蛋白质组学技术为研究细胞的原生微环境提供了新的机会。在这里,我们介绍Giotto,一个全面的开源工具箱,用于空间数据分析和可视化。分析模块通过实现广泛的算法来表征组织组成、空间表达模式和细胞相互作用,提供端到端分析。此外,单细胞RNAseq数据可以集成用于空间细胞型富集分析。可视化模块允许用户交互式地可视化分析输出和成像功能。为了证明其一般适用性,我们将Giotto应用于包括不同技术和平台的广泛数据集。
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引用次数: 337
期刊
Genome Biology
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