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This work integrates long-read sequencing with short-read RNA-seq to map CRC transcriptome complexity, evaluate functions of the TIMP1 Δ4-5 isoform, and test a CRISPR/dCasRx approach to exclude TIMP1 exon 4–5. The study identifies extensive novel transcripts and links differential alternative splicing to prognosis, highlighting TIMP1 Δ4-5 as a potential therapeutic target.",{"@graph":69,"@context":126},[70,84,105],{"@type":71,"itemListElement":72},"BreadcrumbList",[73,77,79,82],{"item":74,"name":75,"@type":76,"position":8},"https://docshare.wps.com","Home","ListItem",{"item":78,"name":9,"@type":76,"position":14},"https://docshare.wps.com/document/",{"item":80,"name":35,"@type":76,"position":81},"https://docshare.wps.com/document/healthcare/",3,{"item":83,"name":65,"@type":76,"position":19},"https://docshare.wps.com/document/long-read-sequencing-reveals-the-landscape-of-aberrant-alternative-splicing-and-novel-therapeutic-target-in-colorectal-cancer-research-paper-summary/386297/",{"url":83,"name":65,"@type":85,"image":86,"author":91,"headline":65,"publisher":94,"fileFormat":97,"inLanguage":63,"description":67,"dateModified":98,"datePublished":99,"encodingFormat":97,"isAccessibleForFree":100,"interactionStatistic":101},"DigitalDocument",{"url":87,"@type":88,"width":89,"height":90},"https://docshare.wps.com/thumbnails/long-read-sequencing-reveals-the-landscape-of-aberrant-alternative-splicing-and-novel-therapeutic-target-in-colorectal-cancer-research-paper-summary/386297.png","ImageObject",300,407,{"name":92,"@type":93},"Cart","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-10-27","2026-09-24",true,{"@type":102,"interactionType":103,"userInteractionCount":34},"InteractionCounter",{"@type":104},"ViewAction",{"@type":106,"mainEntity":107},"FAQPage",[108,114,118,122],{"name":109,"@type":110,"acceptedAnswer":111},"What is the main focus of this study in colorectal cancer?","Question",{"text":112,"@type":113},"The study characterizes the CRC landscape of aberrant alternative splicing using long-read sequencing and identifies novel therapeutic relevance of specific splicing events, especially TIMP1 exon 4–5 exclusion.","Answer",{"name":115,"@type":110,"acceptedAnswer":116},"How did the researchers identify novel splicing events?",{"text":117,"@type":113},"They combined long-read sequencing with short-read RNA-seq to investigate transcriptome complexity and determine which transcripts were novel relative to existing annotations.",{"name":119,"@type":110,"acceptedAnswer":120},"What role does the splicing isoform TIMP1 Δ4-5 play in CRC?",{"text":121,"@type":113},"TIMP1 Δ4-5 is significantly downregulated in CRC, and functional assays show that ectopic expression suppresses tumor cell growth and metastasis, supporting its relevance to disease progression.",{"name":123,"@type":110,"acceptedAnswer":124},"How can TIMP1 exon 4–5 exclusion be targeted therapeutically?",{"text":125,"@type":113},"The study introduces a CRISPR/dCasRx-based strategy to induce TIMP1 exon 4–5 exclusion, and reports that such approaches have potential to restrain CRC growth.","https://schema.org",{"og:url":83,"og:type":128,"og:title":65,"og:site_name":95,"og:description":67},"article",{"robots":130,"canonical":83},"index,follow",{"doc_id":132,"site_id":62},386297,1790834851,{"code":4,"msg":5,"data":135},{"doc_id":132,"user_id":136,"nickname":92,"user_avatar":137,"doc_module":4,"category_id":34,"category_name":35,"doc_title":65,"doc_description":67,"doc_content":138,"file_id":139,"file_url":140,"file_type":141,"file_size":142,"view_count":34,"is_deleted":4,"is_public":8,"is_downloadable":8,"audit_status":8,"page_count":143,"language":144,"language_code":63,"site_id":62,"html_lang":63,"table_of_contents":145,"faqs":146,"seo_title":147,"seo_description":67,"update_tm":148,"read_time":26},18829141979164,"https://eur-avatar.wpscdn.com/davatar_6f874abed73319feea01a86fa6f0fab8","Sun et al. Genome Medicine (2023) 15:76 [https://doi.org/10.1186/s13073-023-01226-y](https://doi.org/10.1186/s13073-023-01226-y)  \nGenome Medicine  \n RESEARCH Open Access  \nLong-read sequencing reveals the landscape of aberrant alternative splicing and novel therapeutic target in colorectal cancer  \nQiang Sun1,2,3,4†, Ye Han5†, Jianxing He1†, Jie Wang1, Xuejie Ma1, Qianqian Ning1, Qing Zhao1, Qian Jin1, Lili Yang1, Shuang Li4, Yang Li6, Qiaoming Zhi5*, Junnian Zheng2,3* and Dong Dong1,2,3*  \nAbstract  \nBackground Alternative splicing complexity plays a vital role in carcinogenesis and cancer progression. Improved understanding of novel splicing events and the underlying regulatory mechanisms may contribute new insights into developing new therapeutic strategies for colorectal cancer (CRC) .  \nMethods Here, we combined long-read sequencing technology with short-read RNA-seq methods to investigate the transcriptome complexity in CRC. By using experiment assays, we explored the function of newly identified splicing isoform TIMP1 Δ4-5. Moreover, a CRISPR/dCasRx-based strategy to induce the TIMP1 exon 4–5 exclusion was introduced to inhibit neoplasm growth.  \nResults A total of 90,703 transcripts were identified, of which > 62% were novel compared with current transcriptome annotations. These novel transcripts were more likely to be sample specific, expressed at relatively lower levels with more exons, and oncogenes displayed a characteristic to generate more transcripts in CRC. Clinical outcome data analysis showed that 1472 differentially expressed alternative splicing events (DEAS) were tightly associated with CRC patients’ prognosis, and many novel isoforms were likely to be important determinants for patient survival. Among these, newly identified splicing isoform TIMP1 Δ4-5 was significantly downregulated in CRC. Further in vitro and in vivo assays demonstrated that ectopic expression of TIMP1 Δ4-5 significantly suppresses tumor cell growth and metastasis. Serine/arginine-rich splicing factor 1 (SRSF1) acts as a onco-splicing regulator through sustaining the inclusion of TIMP1 exon 4–5. Furthermore, CRISPR/dCasRx-based strategies designed to induce TIMP1 exon 4–5 exclusion have the potential to restrain the CRC growth.  \nConclusions This data provides a rich resource for deeper studies of gastrointestinal malignancies. Newly identified splicing isoform TIMP1 Δ4-5 plays an important role in mediating CRC progression and may be a potential therapy target in CRC.  \nKeywords Long-read sequencing, Alternative splicing, TIMP1 Δ4-5, Colorectal cancer  \n†Qiang Sun, Ye Han and Jianxing He contributed equally to this work.  \n*Correspondence: Qiaoming Zhi [strexboy@163.com](strexboy@163.com)[ ](strexboy@163.com)Junnian Zheng [jnzheng@xzhmu.edu.cn](jnzheng@xzhmu.edu.cn)[ ](jnzheng@xzhmu.edu.cn)Dong Dong [ddong@xzhmu.edu.cn](ddong@xzhmu.edu.cn)  \nFull list of author information is available at the end of the article  \n© The Author(s) 2023. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit [http://creativecommons.org/licenses/by/4.0/](http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver ()[. The Creative Commons Public Domain Dedication waiver (](http://","cbCaicYAHqDsbsYm","https://ap.wps.com/l/cbCaicYAHqDsbsYm","pdf",5209133,24,"English","# Abstract\n## Background\n## Methods\n## Results\n## Conclusions\n# Introduction\n## Alternative splicing in cancer\n## Alternative splicing in colorectal cancer\n## Challenges in systematic identification","[{\"question\":\"What is the main focus of this study in colorectal cancer?\",\"answer\":\"The study characterizes the CRC landscape of aberrant alternative splicing using long-read sequencing and identifies novel therapeutic relevance of specific splicing events, especially TIMP1 exon 4–5 exclusion.\"},{\"question\":\"How did the researchers identify novel splicing events?\",\"answer\":\"They combined long-read sequencing with short-read RNA-seq to investigate transcriptome complexity and determine which transcripts were novel relative to existing annotations.\"},{\"question\":\"What role does the splicing isoform TIMP1 Δ4-5 play in CRC?\",\"answer\":\"TIMP1 Δ4-5 is significantly downregulated in CRC, and functional assays show that ectopic expression suppresses tumor cell growth and metastasis, supporting its relevance to disease progression.\"},{\"question\":\"How can TIMP1 exon 4–5 exclusion be targeted therapeutically?\",\"answer\":\"The study introduces a CRISPR/dCasRx-based strategy to induce TIMP1 exon 4–5 exclusion, and reports that such approaches have potential to restrain CRC growth.\"}]","Long-read sequencing reveals the landscape of aberrant alternative splicing and novel therapeutic target in colorectal cancer - research paper summary | PDF",1790273168]