Genome Biology最新文献_第5页

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

Genome Biology 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

{"title":"Prevention of acquired sensorineural hearing loss in mice by in vivo Htra2 gene editing.","authors":"Xi Gu, Daqi Wang, Zhijiao Xu, Jinghan Wang, Luo Guo, Renjie Chai, Genglin Li, Yilai Shu, Huawei Li","doi":"10.1186/s13059-021-02311-4","DOIUrl":"10.1186/s13059-021-02311-4","url":null,"abstract":"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.","PeriodicalId":48922,"journal":{"name":"Genome Biology","volume":"22 1","pages":"86"},"PeriodicalIF":12.3,"publicationDate":"2021-03-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7983387/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"25505755","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: 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

Genome Biology 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

{"title":"Histone lactylation drives oncogenesis by facilitating m6A reader protein YTHDF2 expression in ocular melanoma.","authors":"Jie Yu, Peiwei Chai, Minyue Xie, Shengfang Ge, Jing Ruan, Xianqun Fan, Renbing Jia","doi":"10.1186/s13059-021-02308-z","DOIUrl":"https://doi.org/10.1186/s13059-021-02308-z","url":null,"abstract":"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.","PeriodicalId":48922,"journal":{"name":"Genome Biology","volume":"22 1","pages":"85"},"PeriodicalIF":12.3,"publicationDate":"2021-03-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1186/s13059-021-02308-z","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"25484292","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: 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

Genome Biology 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

{"title":"Prime editing in mice reveals the essentiality of a single base in driving tissue-specific gene expression.","authors":"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","doi":"10.1186/s13059-021-02304-3","DOIUrl":"10.1186/s13059-021-02304-3","url":null,"abstract":"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.","PeriodicalId":48922,"journal":{"name":"Genome Biology","volume":"22 1","pages":"83"},"PeriodicalIF":12.3,"publicationDate":"2021-03-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7962346/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"25480710","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: 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

Genome Biology Pub Date : 2021-03-16 DOI: 10.1186/s13059-021-02303-4

Huiguang Yi, Yanling Lin, Chengqi Lin, Wenfei Jin

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

Genome Biology 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

{"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, 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","doi":"10.1186/s13059-021-02298-y","DOIUrl":"https://doi.org/10.1186/s13059-021-02298-y","url":null,"abstract":"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.","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

Genome Biology Pub Date : 2021-03-10 DOI: 10.1186/s13059-021-02295-1

Johannes Zimmermann, Christoph Kaleta, Silvio Waschina

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

Genome Biology Pub Date : 2021-03-10 DOI: 10.1186/s13059-021-02305-2

Changcai Huang, Guangyu Li, Jiayu Wu, Junbo Liang, Xiaoyue Wang

{"title":"Identification of pathogenic variants in cancer genes using base editing screens with editing efficiency correction.","authors":"Changcai Huang, Guangyu Li, Jiayu Wu, Junbo Liang, Xiaoyue Wang","doi":"10.1186/s13059-021-02305-2","DOIUrl":"10.1186/s13059-021-02305-2","url":null,"abstract":"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.","PeriodicalId":48922,"journal":{"name":"Genome Biology","volume":"22 1","pages":"80"},"PeriodicalIF":12.3,"publicationDate":"2021-03-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7945310/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"25454348","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: 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

Genome Biology Pub Date : 2021-03-09 DOI: 10.1186/s13059-021-02287-1

Eddie Park, Yan Jiang, Lili Hao, Jingyi Hui, Yi Xing

{"title":"Genetic variation and microRNA targeting of A-to-I RNA editing fine tune human tissue transcriptomes.","authors":"Eddie Park, Yan Jiang, Lili Hao, Jingyi Hui, Yi Xing","doi":"10.1186/s13059-021-02287-1","DOIUrl":"10.1186/s13059-021-02287-1","url":null,"abstract":"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.","PeriodicalId":48922,"journal":{"name":"Genome Biology","volume":"22 1","pages":"77"},"PeriodicalIF":12.3,"publicationDate":"2021-03-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7942016/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"25464351","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: 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

Genome Biology Pub Date : 2021-03-08 DOI: 10.1186/s13059-021-02300-7

Huihui Li, Mingzhe Xie, Yan Wang, Ludong Yang, Zhi Xie, Hongwei Wang

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

Genome Biology 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

引用次数: 337