{"title":"ΔNp63β的差异转录活性是由一个同工型特异性c端编码的。","authors":"Abby A McCann, Morgan A Sammons","doi":"10.1080/10985549.2025.2514529","DOIUrl":null,"url":null,"abstract":"<p><p>p63 is a clinically relevant transcription factor heavily involved in development and disease. Mutations in the p63 DNA-binding domain cause severe developmental defects and overexpression of p63 plays a role in the progression of epithelial-associated cancers. Unraveling the specific biochemical mechanisms underlying these phenotypes is made challenging by the presence of multiple p63 isoforms and their shared and unique contributions to development and disease. Here, we explore the function of the p63 isoforms ΔNp63ɑ and ΔNp63β to determine the contribution of C-terminal splice variants on known and unique molecular and biochemical activities. Using RNA-seq and ChIP-seq on isoform-specific cell lines, we show that ΔNp63β regulates both canonical ΔNp63ɑ targets and a unique set of genes with varying biological functions. We demonstrate that most genomic binding sites are shared, however the enhancer-associated histone modification H3K27ac is highly enriched at ΔNp63β binding sites relative to ΔNp63ɑ. An array of ΔNp63β C-terminal mutants demonstrates the importance of isoform-specific C-terminal domains in regulating these unique activities. Our results provide novel insight into differential activities of p63 C-terminal isoforms and suggest future directions for dissecting the functional relevance of these and other transcription factor isoforms in development and disease.</p>","PeriodicalId":18658,"journal":{"name":"Molecular and Cellular Biology","volume":" ","pages":"1-17"},"PeriodicalIF":2.7000,"publicationDate":"2025-06-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12288839/pdf/","citationCount":"0","resultStr":"{\"title\":\"Differential Transcriptional Activity of ΔNp63β Is Encoded by an Isoform-Specific C-Terminus.\",\"authors\":\"Abby A McCann, Morgan A Sammons\",\"doi\":\"10.1080/10985549.2025.2514529\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>p63 is a clinically relevant transcription factor heavily involved in development and disease. Mutations in the p63 DNA-binding domain cause severe developmental defects and overexpression of p63 plays a role in the progression of epithelial-associated cancers. Unraveling the specific biochemical mechanisms underlying these phenotypes is made challenging by the presence of multiple p63 isoforms and their shared and unique contributions to development and disease. Here, we explore the function of the p63 isoforms ΔNp63ɑ and ΔNp63β to determine the contribution of C-terminal splice variants on known and unique molecular and biochemical activities. Using RNA-seq and ChIP-seq on isoform-specific cell lines, we show that ΔNp63β regulates both canonical ΔNp63ɑ targets and a unique set of genes with varying biological functions. We demonstrate that most genomic binding sites are shared, however the enhancer-associated histone modification H3K27ac is highly enriched at ΔNp63β binding sites relative to ΔNp63ɑ. An array of ΔNp63β C-terminal mutants demonstrates the importance of isoform-specific C-terminal domains in regulating these unique activities. Our results provide novel insight into differential activities of p63 C-terminal isoforms and suggest future directions for dissecting the functional relevance of these and other transcription factor isoforms in development and disease.</p>\",\"PeriodicalId\":18658,\"journal\":{\"name\":\"Molecular and Cellular Biology\",\"volume\":\" \",\"pages\":\"1-17\"},\"PeriodicalIF\":2.7000,\"publicationDate\":\"2025-06-23\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12288839/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Molecular and Cellular Biology\",\"FirstCategoryId\":\"99\",\"ListUrlMain\":\"https://doi.org/10.1080/10985549.2025.2514529\",\"RegionNum\":2,\"RegionCategory\":\"生物学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q2\",\"JCRName\":\"BIOCHEMISTRY & MOLECULAR BIOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Molecular and Cellular Biology","FirstCategoryId":"99","ListUrlMain":"https://doi.org/10.1080/10985549.2025.2514529","RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"BIOCHEMISTRY & MOLECULAR BIOLOGY","Score":null,"Total":0}
引用次数: 0
摘要
P63是临床相关的转录因子,与发育和疾病密切相关。p63 dna结合域的突变导致严重的发育缺陷,p63的过表达在上皮相关癌症的进展中起作用。由于多种p63亚型的存在以及它们对发育和疾病的共同和独特贡献,揭示这些表型背后的特定生化机制具有挑战性。在这里,我们探索p63异构体ΔNp63和ΔNp63β的功能,以确定c端剪接变异体对已知和独特的分子和生化活性的贡献。利用RNA-seq和ChIP-seq对同种异构体特异性细胞系进行分析,我们发现ΔNp63β调控了典型的ΔNp63靶点和一组具有不同生物学功能的独特基因。我们证明了大多数基因组结合位点是共享的,然而增强子相关的组蛋白修饰H3K27ac在ΔNp63β结合位点相对于ΔNp63]高度富集。一系列ΔNp63β c -末端突变体证明了异构体特异性c -末端结构域在调节这些独特活动中的重要性。我们的研究结果为p63 c端异构体的差异活性提供了新的见解,并为解剖这些和其他转录因子异构体在发育和疾病中的功能相关性提供了未来的方向。
Differential Transcriptional Activity of ΔNp63β Is Encoded by an Isoform-Specific C-Terminus.
p63 is a clinically relevant transcription factor heavily involved in development and disease. Mutations in the p63 DNA-binding domain cause severe developmental defects and overexpression of p63 plays a role in the progression of epithelial-associated cancers. Unraveling the specific biochemical mechanisms underlying these phenotypes is made challenging by the presence of multiple p63 isoforms and their shared and unique contributions to development and disease. Here, we explore the function of the p63 isoforms ΔNp63ɑ and ΔNp63β to determine the contribution of C-terminal splice variants on known and unique molecular and biochemical activities. Using RNA-seq and ChIP-seq on isoform-specific cell lines, we show that ΔNp63β regulates both canonical ΔNp63ɑ targets and a unique set of genes with varying biological functions. We demonstrate that most genomic binding sites are shared, however the enhancer-associated histone modification H3K27ac is highly enriched at ΔNp63β binding sites relative to ΔNp63ɑ. An array of ΔNp63β C-terminal mutants demonstrates the importance of isoform-specific C-terminal domains in regulating these unique activities. Our results provide novel insight into differential activities of p63 C-terminal isoforms and suggest future directions for dissecting the functional relevance of these and other transcription factor isoforms in development and disease.
期刊介绍:
Molecular and Cellular Biology (MCB) showcases significant discoveries in cellular morphology and function, genome organization, regulation of genetic expression, morphogenesis, and somatic cell genetics. The journal also examines viral systems, publishing papers that emphasize their impact on the cell.