The intrinsic nature of CRISPR-Cas in conferring immunity to bacteria and archaea has been repurposed to combat pathogenic agents in mammalian and plant cells. In this regard, CRISPR-Cas13 systems have proved their remarkable potential for single-strand RNA viruses targeting. Here, different types of Cas13 orthologs were applied to knockdown foot-and-mouth disease virus (FMDV), a highly contagious disease of a wide variety of species with genetically diverse strains and is widely geographically distributed. Using programmable CRISPR RNAs capable of targeting conserved regions of the viral genome, all Cas13s from CRISPR system type VI (subtype A/B/D) could comprehensively target and repress different serotypes of FMDV virus. This approach has the potential to destroy all strains of a virus as targets the ultra-conserved regions of genome. We experimentally compared the silencing efficiency of CRISPR and RNAi by designing the most effective short hairpin RNAs according to our developed scoring system and observed comparable results. This study showed successful usage of various Cas13 enzymes for suppression of FMDV, which provides a flexible strategy to battle with other animal infectious RNA viruses, an underdeveloped field in the biotechnology scope.
{"title":"Protection of animals against devastating RNA viruses using CRISPR-Cas13s","authors":"Adnan Asadbeigi, Mohammad Reza Bakhtiarizadeh, Mojtaba Saffari, Mohammad Hossein Modarressi, Naser Sadri, Zahra Ziafati Kafi, Hassan Fazilaty, Arash Ghalyanchilangeroudi, Hossein Esmaeili","doi":"10.1016/j.omtn.2024.102235","DOIUrl":"https://doi.org/10.1016/j.omtn.2024.102235","url":null,"abstract":"The intrinsic nature of CRISPR-Cas in conferring immunity to bacteria and archaea has been repurposed to combat pathogenic agents in mammalian and plant cells. In this regard, CRISPR-Cas13 systems have proved their remarkable potential for single-strand RNA viruses targeting. Here, different types of Cas13 orthologs were applied to knockdown foot-and-mouth disease virus (FMDV), a highly contagious disease of a wide variety of species with genetically diverse strains and is widely geographically distributed. Using programmable CRISPR RNAs capable of targeting conserved regions of the viral genome, all Cas13s from CRISPR system type VI (subtype A/B/D) could comprehensively target and repress different serotypes of FMDV virus. This approach has the potential to destroy all strains of a virus as targets the ultra-conserved regions of genome. We experimentally compared the silencing efficiency of CRISPR and RNAi by designing the most effective short hairpin RNAs according to our developed scoring system and observed comparable results. This study showed successful usage of various Cas13 enzymes for suppression of FMDV, which provides a flexible strategy to battle with other animal infectious RNA viruses, an underdeveloped field in the biotechnology scope.","PeriodicalId":18821,"journal":{"name":"Molecular Therapy. Nucleic Acids","volume":"11 1","pages":""},"PeriodicalIF":8.8,"publicationDate":"2024-05-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141520689","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-05-24DOI: 10.1016/j.omtn.2024.102228
Nikki M. McCormack, Kelsey A. Calabrese, Christina M. Sun, Christopher B. Tully, Christopher R. Heier, Alyson A. Fiorillo
Duchenne muscular dystrophy (DMD) is a progressive muscle disease caused by the absence of dystrophin protein. One current DMD therapeutic strategy, exon skipping, produces a truncated dystrophin isoform using phosphorodiamidate morpholino oligomers (PMOs). However, the potential of exon skipping therapeutics has not been fully realized as increases in dystrophin protein have been minimal in clinical trials. Here, we investigate how miR-146a-5p, which is highly elevated in dystrophic muscle, impacts dystrophin protein levels. We find inflammation strongly induces miR-146a in dystrophic, but not wild-type myotubes. Bioinformatics analysis reveals that the dystrophin 3′ UTR harbors an miR-146a binding site, and subsequent luciferase assays demonstrate miR-146a binding inhibits dystrophin translation. In dystrophin-null mice, co-injection of miR-146a reduces dystrophin restoration by an exon 51 skipping PMO. To directly investigate how miR-146a impacts therapeutic dystrophin rescue, we generated with body-wide miR-146a deletion (). Administration of an exon skipping PMO via intramuscular or intravenous injection markedly increases dystrophin protein levels in vs. muscles; skipped dystrophin transcript levels are unchanged, suggesting a post-transcriptional mechanism of action. Together, these data show that miR-146a expression opposes therapeutic dystrophin restoration, suggesting miR-146a inhibition warrants further research as a potential DMD exon skipping co-therapy.
{"title":"Deletion of miR-146a enhances therapeutic protein restoration in model of dystrophin exon skipping","authors":"Nikki M. McCormack, Kelsey A. Calabrese, Christina M. Sun, Christopher B. Tully, Christopher R. Heier, Alyson A. Fiorillo","doi":"10.1016/j.omtn.2024.102228","DOIUrl":"https://doi.org/10.1016/j.omtn.2024.102228","url":null,"abstract":"Duchenne muscular dystrophy (DMD) is a progressive muscle disease caused by the absence of dystrophin protein. One current DMD therapeutic strategy, exon skipping, produces a truncated dystrophin isoform using phosphorodiamidate morpholino oligomers (PMOs). However, the potential of exon skipping therapeutics has not been fully realized as increases in dystrophin protein have been minimal in clinical trials. Here, we investigate how miR-146a-5p, which is highly elevated in dystrophic muscle, impacts dystrophin protein levels. We find inflammation strongly induces miR-146a in dystrophic, but not wild-type myotubes. Bioinformatics analysis reveals that the dystrophin 3′ UTR harbors an miR-146a binding site, and subsequent luciferase assays demonstrate miR-146a binding inhibits dystrophin translation. In dystrophin-null mice, co-injection of miR-146a reduces dystrophin restoration by an exon 51 skipping PMO. To directly investigate how miR-146a impacts therapeutic dystrophin rescue, we generated with body-wide miR-146a deletion (). Administration of an exon skipping PMO via intramuscular or intravenous injection markedly increases dystrophin protein levels in vs. muscles; skipped dystrophin transcript levels are unchanged, suggesting a post-transcriptional mechanism of action. Together, these data show that miR-146a expression opposes therapeutic dystrophin restoration, suggesting miR-146a inhibition warrants further research as a potential DMD exon skipping co-therapy.","PeriodicalId":18821,"journal":{"name":"Molecular Therapy. Nucleic Acids","volume":"26 1","pages":""},"PeriodicalIF":8.8,"publicationDate":"2024-05-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141256316","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-05-03DOI: 10.1016/j.omtn.2024.102205
Kirti Prasad, Nivedhitha Devaraju, Anila George, Nithin Sam Ravi, Joshua Paul P, Gokulnath Mahalingam, Vignesh Rajendiran, Lokesh Panigrahi, Vigneshwaran Venkatesan, Kartik Lakhotiya, Yogapriya Periyasami, Aswin Anand Pai, Yukio Nakamura, Ryo Kurita, Poonkuzhali Balasubramanian, Saravanabhavan Thangavel, Shaji R. Velayudhan, Gregory A. Newby, Srujan Marepally, Alok Srivastava, Kumarasamypet M. Mohankumar
β-thalassemia/HbE results from mutations in the β-globin locus that impede the production of functional adult hemoglobin. Base editors (BEs) could facilitate the correction of the point mutations with minimal or no indel creation, but its efficiency and bystander editing for the correction of β-thalassemia mutations in coding and non-coding regions remains unexplored. Here, we screened BE variants in HUDEP-2 cells for their ability to correct a spectrum of β-thalassemia mutations that were integrated into the genome as fragments of . The identified targets were introduced into their endogenous genomic location using BEs and Cas9/homology-directed repair (HDR) to create cellular models with β-thalassemia. These β-thalassemia models were then used to assess the efficiency of correction in the native locus and functional β-globin restoration. Most bystander edits produced near target sites did not interfere with adult hemoglobin expression and are not predicted to be pathogenic. Further, the effectiveness of BE was validated for the correction of the pathogenic HbE variant in severe β/β-thalassaemia patient cells. Overall, our study establishes a novel platform to screen and select optimal BE tools for therapeutic genome editing by demonstrating the precise, efficient, and scarless correction of pathogenic point mutations spanning multiple regions of including the promoter, intron, and exons.
β-地中海贫血/HbE 是由β-球蛋白基因座中的突变导致的，这些突变阻碍了功能性成人血红蛋白的生成。碱基编辑器（BEs）可以促进点突变的校正，而只产生极少或不产生滞后点，但其校正编码区和非编码区β-地中海贫血突变的效率和旁观者编辑仍有待探索。在这里，我们筛选了 HUDEP-2 细胞中的 BE 变体，以确定它们是否能纠正以片段形式整合到基因组中的β-地中海贫血突变。 使用 BE 和 Cas9/同源定向修复（HDR）将确定的靶标导入其内源性基因组位置，以创建β-地中海贫血细胞模型。这些β-地中海贫血症模型随后被用来评估原生基因座的校正效率和β-球蛋白的功能恢复。在目标位点附近产生的大多数旁观者编辑不会干扰成体血红蛋白的表达，也不会致病。此外，我们还验证了 BE 在纠正重度β/β-地中海贫血患者细胞中致病性 HbE 变异方面的有效性。总之，我们的研究建立了一个新的平台，通过精确、高效、无疤痕地校正跨启动子、内含子和外显子等多个区域的致病点突变，筛选出用于治疗性基因组编辑的最佳 BE 工具。
{"title":"Precise correction of a spectrum of β-thalassemia mutations in coding and non-coding regions by base editors","authors":"Kirti Prasad, Nivedhitha Devaraju, Anila George, Nithin Sam Ravi, Joshua Paul P, Gokulnath Mahalingam, Vignesh Rajendiran, Lokesh Panigrahi, Vigneshwaran Venkatesan, Kartik Lakhotiya, Yogapriya Periyasami, Aswin Anand Pai, Yukio Nakamura, Ryo Kurita, Poonkuzhali Balasubramanian, Saravanabhavan Thangavel, Shaji R. Velayudhan, Gregory A. Newby, Srujan Marepally, Alok Srivastava, Kumarasamypet M. Mohankumar","doi":"10.1016/j.omtn.2024.102205","DOIUrl":"https://doi.org/10.1016/j.omtn.2024.102205","url":null,"abstract":"β-thalassemia/HbE results from mutations in the β-globin locus that impede the production of functional adult hemoglobin. Base editors (BEs) could facilitate the correction of the point mutations with minimal or no indel creation, but its efficiency and bystander editing for the correction of β-thalassemia mutations in coding and non-coding regions remains unexplored. Here, we screened BE variants in HUDEP-2 cells for their ability to correct a spectrum of β-thalassemia mutations that were integrated into the genome as fragments of . The identified targets were introduced into their endogenous genomic location using BEs and Cas9/homology-directed repair (HDR) to create cellular models with β-thalassemia. These β-thalassemia models were then used to assess the efficiency of correction in the native locus and functional β-globin restoration. Most bystander edits produced near target sites did not interfere with adult hemoglobin expression and are not predicted to be pathogenic. Further, the effectiveness of BE was validated for the correction of the pathogenic HbE variant in severe β/β-thalassaemia patient cells. Overall, our study establishes a novel platform to screen and select optimal BE tools for therapeutic genome editing by demonstrating the precise, efficient, and scarless correction of pathogenic point mutations spanning multiple regions of including the promoter, intron, and exons.","PeriodicalId":18821,"journal":{"name":"Molecular Therapy. Nucleic Acids","volume":"20 1","pages":""},"PeriodicalIF":8.8,"publicationDate":"2024-05-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140939370","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-04-29DOI: 10.1016/j.omtn.2024.102206
Mansi A. Parasrampuria, Adam A. White, Ramadevi Chilamkurthy, Adrian A. Pater, Fatima El-Azzouzi, Katy N. Ovington, Philip J. Jensik, Keith T. Gagnon
Huntington’s disease (HD) is an incurable neurodegenerative disorder caused by genetic expansion of a CAG repeat sequence in one allele of the (HTT) gene. Reducing expression of the mutant HTT (mutHTT) protein has remained a clear therapeutic goal, but reduction of wild-type HTT is undesirable, as it compromises gene function and potential therapeutic efficacy. One promising allele-selective approach involves targeting the CAG repeat expansion with steric binding small RNAs bearing central mismatches. However, successful genetic encoding requires consistent placement of mismatches to the target within the small RNA guide sequence, which involves 5′ processing precision by cellular enzymes. Here, we used small RNA sequencing (RNA-seq) to monitor the processing precision of a limited set of CAG repeat-targeted small RNAs expressed from multiple scaffold contexts. Small RNA-seq identified expression constructs with high-guide strand 5′ processing precision and promising allele-selective inhibition of mutHTT. Transcriptome-wide mRNA-seq also identified an allele-selective small RNA with a favorable off-target profile. These results support continued investigation and optimization of genetically encoded repeat-targeted small RNAs for allele-selective HD gene therapy and underscore the value of sequencing methods to balance specificity with allele selectivity during the design and selection process.
{"title":"Sequencing-guided design of genetically encoded small RNAs targeting CAG repeats for selective inhibition of mutant huntingtin","authors":"Mansi A. Parasrampuria, Adam A. White, Ramadevi Chilamkurthy, Adrian A. Pater, Fatima El-Azzouzi, Katy N. Ovington, Philip J. Jensik, Keith T. Gagnon","doi":"10.1016/j.omtn.2024.102206","DOIUrl":"https://doi.org/10.1016/j.omtn.2024.102206","url":null,"abstract":"Huntington’s disease (HD) is an incurable neurodegenerative disorder caused by genetic expansion of a CAG repeat sequence in one allele of the (HTT) gene. Reducing expression of the mutant HTT (mutHTT) protein has remained a clear therapeutic goal, but reduction of wild-type HTT is undesirable, as it compromises gene function and potential therapeutic efficacy. One promising allele-selective approach involves targeting the CAG repeat expansion with steric binding small RNAs bearing central mismatches. However, successful genetic encoding requires consistent placement of mismatches to the target within the small RNA guide sequence, which involves 5′ processing precision by cellular enzymes. Here, we used small RNA sequencing (RNA-seq) to monitor the processing precision of a limited set of CAG repeat-targeted small RNAs expressed from multiple scaffold contexts. Small RNA-seq identified expression constructs with high-guide strand 5′ processing precision and promising allele-selective inhibition of mutHTT. Transcriptome-wide mRNA-seq also identified an allele-selective small RNA with a favorable off-target profile. These results support continued investigation and optimization of genetically encoded repeat-targeted small RNAs for allele-selective HD gene therapy and underscore the value of sequencing methods to balance specificity with allele selectivity during the design and selection process.","PeriodicalId":18821,"journal":{"name":"Molecular Therapy. Nucleic Acids","volume":"42 1","pages":""},"PeriodicalIF":8.8,"publicationDate":"2024-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140939373","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-04-26DOI: 10.1016/j.omtn.2024.102202
Manoj Kumar Kashyap, Hiren Karathia, Deepak Kumar, Roberto Vera Alvarez, Jose Vicente Forero-Forero, Eider Moreno, Juliana Velez Lujan, Carlos Ivan Amaya-Chanaga, Newton Medeiros Vidal, Zhe Yu, Emanuela M. Ghia, Paula A. Lengerke-Diaz, Daniel Achinko, Michael Y. Choi, Laura Z. Rassenti, Leonardo Mariño-Ramírez, Stephen M. Mount, Sridhar Hannenhalli, Thomas J. Kipps, Januario E. Castro
Splicing factor 3b subunit 1 (SF3B1) is the largest subunit and core component of the spliceosome. Inhibition of SF3B1 was associated with an increase in broad intron retention (IR) on most transcripts, suggesting that IR can be used as a marker of spliceosome inhibition in chronic lymphocytic leukemia (CLL) cells. Furthermore, we separately analyzed exonic and intronic mapped reads on annotated RNA-sequencing transcripts obtained from B cells ( = 98 CLL patients) and healthy volunteers ( = 09). We measured intron/exon ration to use that as a surrogate for alternative RNA splicing (ARS) and found that 66% of CLL-B cell transcripts had significant IR elevation compared with normal B cells (NBCs) and that correlated with mRNA downregulation and low expression levels. Transcripts with highest IR levels belonged to biological pathways associated with gene expression and RNA splicing. A >2-fold increase of active pSF3B1 in CLL-B cells compared with NBCs. Additionally, when the CLL-B cells were treated with macrolides (pladienolide-B), a significant decrease in pSF3B1, but not total SF3B1 protein was observed. These findings suggest that IR/ARS is increased in CLL, which is associated with SF3B1 phosphorylation and susceptibility to SF3B1 inhibitors. These data provide additional support to the relevance of ARS in carcinogenesis and evidence of pSF3B1 participation in this process.
{"title":"Aberrant spliceosome activity via elevated intron retention and upregulation and phosphorylation of SF3B1 in chronic lymphocytic leukemia","authors":"Manoj Kumar Kashyap, Hiren Karathia, Deepak Kumar, Roberto Vera Alvarez, Jose Vicente Forero-Forero, Eider Moreno, Juliana Velez Lujan, Carlos Ivan Amaya-Chanaga, Newton Medeiros Vidal, Zhe Yu, Emanuela M. Ghia, Paula A. Lengerke-Diaz, Daniel Achinko, Michael Y. Choi, Laura Z. Rassenti, Leonardo Mariño-Ramírez, Stephen M. Mount, Sridhar Hannenhalli, Thomas J. Kipps, Januario E. Castro","doi":"10.1016/j.omtn.2024.102202","DOIUrl":"https://doi.org/10.1016/j.omtn.2024.102202","url":null,"abstract":"Splicing factor 3b subunit 1 (SF3B1) is the largest subunit and core component of the spliceosome. Inhibition of SF3B1 was associated with an increase in broad intron retention (IR) on most transcripts, suggesting that IR can be used as a marker of spliceosome inhibition in chronic lymphocytic leukemia (CLL) cells. Furthermore, we separately analyzed exonic and intronic mapped reads on annotated RNA-sequencing transcripts obtained from B cells ( = 98 CLL patients) and healthy volunteers ( = 09). We measured intron/exon ration to use that as a surrogate for alternative RNA splicing (ARS) and found that 66% of CLL-B cell transcripts had significant IR elevation compared with normal B cells (NBCs) and that correlated with mRNA downregulation and low expression levels. Transcripts with highest IR levels belonged to biological pathways associated with gene expression and RNA splicing. A >2-fold increase of active pSF3B1 in CLL-B cells compared with NBCs. Additionally, when the CLL-B cells were treated with macrolides (pladienolide-B), a significant decrease in pSF3B1, but not total SF3B1 protein was observed. These findings suggest that IR/ARS is increased in CLL, which is associated with SF3B1 phosphorylation and susceptibility to SF3B1 inhibitors. These data provide additional support to the relevance of ARS in carcinogenesis and evidence of pSF3B1 participation in this process.","PeriodicalId":18821,"journal":{"name":"Molecular Therapy. Nucleic Acids","volume":"7 1","pages":""},"PeriodicalIF":8.8,"publicationDate":"2024-04-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140889393","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-04-06DOI: 10.1016/j.omtn.2024.102186
Gyeongjo Hwang, Mincheol Kwon, Dongjin Seo, Dae Hoon Kim, Daehwan Lee, Kiwon Lee, Eunyoung Kim, Mingeun Kang, Jin-Hyeob Ryu
Recent studies have highlighted the effectiveness of using antisense oligonucleotides (ASOs) for cellular RNA regulation, including targets that are considered undruggable; however, manually designing optimal ASO sequences can be labor intensive and time consuming, which potentially limits their broader application. To address this challenge, we introduce a platform, the ASOptimizer, a deep-learning-based framework that efficiently designs ASOs at a low cost. This platform not only selects the most efficient mRNA target sites but also optimizes the chemical modifications for enhanced performance. Indoleamine 2,3-dioxygenase 1 (IDO1) promotes cancer survival by depleting tryptophan and producing kynurenine, leading to immunosuppression through the AhR pathway within the tumor microenvironment. We used ASOptimizer to identify ASOs that target IDO1 mRNA as potential cancer therapeutics. Our methodology consists of two stages: sequence engineering and chemical engineering. During the sequence-engineering stage, we optimized and predicted ASO sequences that could target IDO1 mRNA efficiently. In the chemical-engineering stage, we further refined these ASOs to enhance their inhibitory activity while reducing their potential cytotoxicity. In conclusion, our research demonstrates the potential of ASOptimizer for identifying ASOs with improved efficacy and safety.
{"title":"ASOptimizer: Optimizing antisense oligonucleotides through deep learning for IDO1 gene regulation","authors":"Gyeongjo Hwang, Mincheol Kwon, Dongjin Seo, Dae Hoon Kim, Daehwan Lee, Kiwon Lee, Eunyoung Kim, Mingeun Kang, Jin-Hyeob Ryu","doi":"10.1016/j.omtn.2024.102186","DOIUrl":"https://doi.org/10.1016/j.omtn.2024.102186","url":null,"abstract":"Recent studies have highlighted the effectiveness of using antisense oligonucleotides (ASOs) for cellular RNA regulation, including targets that are considered undruggable; however, manually designing optimal ASO sequences can be labor intensive and time consuming, which potentially limits their broader application. To address this challenge, we introduce a platform, the ASOptimizer, a deep-learning-based framework that efficiently designs ASOs at a low cost. This platform not only selects the most efficient mRNA target sites but also optimizes the chemical modifications for enhanced performance. Indoleamine 2,3-dioxygenase 1 (IDO1) promotes cancer survival by depleting tryptophan and producing kynurenine, leading to immunosuppression through the AhR pathway within the tumor microenvironment. We used ASOptimizer to identify ASOs that target IDO1 mRNA as potential cancer therapeutics. Our methodology consists of two stages: sequence engineering and chemical engineering. During the sequence-engineering stage, we optimized and predicted ASO sequences that could target IDO1 mRNA efficiently. In the chemical-engineering stage, we further refined these ASOs to enhance their inhibitory activity while reducing their potential cytotoxicity. In conclusion, our research demonstrates the potential of ASOptimizer for identifying ASOs with improved efficacy and safety.","PeriodicalId":18821,"journal":{"name":"Molecular Therapy. Nucleic Acids","volume":"47 1","pages":""},"PeriodicalIF":8.8,"publicationDate":"2024-04-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140586172","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-04-06DOI: 10.1016/j.omtn.2024.102187
Xinyu Zhang, Mingzhe Liu, Zhen Li, Linlin Zhuo, Xiangzheng Fu, Quan Zou
Long non-coding RNAs (lncRNAs) are important factors involved in biological regulatory networks. Accurately predicting lncRNA-protein interactions (LPIs) is vital for clarifying lncRNA’s functions and pathogenic mechanisms. Existing deep learning models have yet to yield satisfactory results in LPI prediction. Recently, graph autoencoders (GAEs) have seen rapid development, excelling in tasks like link prediction and node classification. We employed GAE technology for LPI prediction, devising the FMSRT-LPI model based on path masking and degree regression strategies and thereby achieving satisfactory outcomes. This represents the first known integration of path masking and degree regression strategies into the GAE framework for potential LPI inference. The effectiveness of our FMSRT-LPI model primarily relies on four key aspects. First, within the GAE framework, our model integrates multi-source relationships of lncRNAs and proteins with LPN’s topological data. Second, the implemented masking strategy efficiently identifies LPN’s key paths, reconstructs the network, and reduces the impact of redundant or incorrect data. Third, the integrated degree decoder balances degree and structural information, enhancing node representation. Fourth, the PolyLoss function we introduced is more appropriate for LPI prediction tasks. The results on multiple public datasets further demonstrate our model’s potential in LPI prediction. Our code and data can be freely accessed at .
{"title":"Fusion of multi-source relationships and topology to infer lncRNA-protein interactions","authors":"Xinyu Zhang, Mingzhe Liu, Zhen Li, Linlin Zhuo, Xiangzheng Fu, Quan Zou","doi":"10.1016/j.omtn.2024.102187","DOIUrl":"https://doi.org/10.1016/j.omtn.2024.102187","url":null,"abstract":"Long non-coding RNAs (lncRNAs) are important factors involved in biological regulatory networks. Accurately predicting lncRNA-protein interactions (LPIs) is vital for clarifying lncRNA’s functions and pathogenic mechanisms. Existing deep learning models have yet to yield satisfactory results in LPI prediction. Recently, graph autoencoders (GAEs) have seen rapid development, excelling in tasks like link prediction and node classification. We employed GAE technology for LPI prediction, devising the FMSRT-LPI model based on path masking and degree regression strategies and thereby achieving satisfactory outcomes. This represents the first known integration of path masking and degree regression strategies into the GAE framework for potential LPI inference. The effectiveness of our FMSRT-LPI model primarily relies on four key aspects. First, within the GAE framework, our model integrates multi-source relationships of lncRNAs and proteins with LPN’s topological data. Second, the implemented masking strategy efficiently identifies LPN’s key paths, reconstructs the network, and reduces the impact of redundant or incorrect data. Third, the integrated degree decoder balances degree and structural information, enhancing node representation. Fourth, the PolyLoss function we introduced is more appropriate for LPI prediction tasks. The results on multiple public datasets further demonstrate our model’s potential in LPI prediction. Our code and data can be freely accessed at .","PeriodicalId":18821,"journal":{"name":"Molecular Therapy. Nucleic Acids","volume":"38 1","pages":""},"PeriodicalIF":8.8,"publicationDate":"2024-04-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140585985","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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