Risk SNP in a transcript of RP11-638I2.4 increases lncRNA-YY1 interaction and pancreatic cancer susceptibility
Risk SNP in a transcript of RP11-638I2.4 increases lncRNA-YY1 interaction and pancreatic cancer susceptibility
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DOI：
10.1007/s00204-023-03564-7
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发表时间：
2023-08-16
影响因子：
6.1
通讯作者：
Miao，Xiaoping
中科院分区：
文献类型：
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作者：
Zhang，Ming;Li，Yanmin;Miao，Xiaoping
通过RNA-seq分析已经鉴定出数以万计的长非编码RNA(LncRNAs)，但其生物学和病理学意义尚不清楚。通过整合全基因组的lncRNA数据和对PDAC GWAS的交叉祖先荟萃分析，我们描绘了一个全面的与胰腺导管腺癌(PDAC)相关的lncRNA图谱，包括1,204个lncRNA(445个新的lncRNA和759个GENCODE注释的lncRNA)和4,368个变体。此外，我们发现与PDAC相关的lncRNAs可以通过改变染色质活性、转录因子和RNA结合蛋白的亲和力来发挥作用。重要的是，与PDAC相关的遗传变异优先发现在PDAC相关的lncRNA区域，支持PDAC相关的lncRNAs的生物学和临床相关性。最后，我们优先选择了RP11-638I2.4的新转录本(MICT00000110172.1)作为潜在的肿瘤促进剂，MICT00000110172.1能够增强与YY1的相互作用，从而逆转YY1对胰腺癌细胞周期的抑制作用，从而促进胰腺癌的生长。G >； 在MICT00000110172.1第二外显子的rs2757535处的改变会导致空间结构的改变，并产生YY1结合的靶区，从而以等位基因特异性的方式加强MICT00000110172.1的作用，从而增加肿瘤的易感性。综上所述，我们的结果扩展了与PDAC相关的lncRNA的谱系，可以作为未来功能探索和识别基于lncRNA的靶向治疗的起点。
Tens of thousands of long non-coding RNAs (lncRNAs) have been identified through RNA-seq analysis, but the biological and pathological significance remains unclear. By integrating the genome-wide lncRNA data with a cross-ancestry meta-analysis of PDAC GWASs, we depicted a comprehensive atlas of pancreatic ductal adenocarcinoma (PDAC)-associated lncRNAs, containing 1,204 lncRNA (445 novel lncRNAs and 759 GENCODE annotated lncRNAs) and 4,368 variants. Furthermore, we found that PDAC-associated lncRNAs could function by altering chromatin activity, transcription factors, and RNA-binding proteins binding affinity. Importantly, genetic variants linked to PDAC are preferentially found at PDAC-associated lncRNA regions, supporting the biological and clinical relevance of PDAC-associated lncRNAs. Finally, we prioritized a novel transcript (MICT00000110172.1) ofRP11-638I2.4as a potential tumor promoter.MICT00000110172.1is able to reinforce the interaction with YY1, which could reverse the effect of YY1 on pancreatic cancer cell cycle arrest to promote the pancreatic cancer growth. G > A change at rs2757535 in the second exon ofMICT00000110172.1induces a spatial structural change and creates a target region for YY1 binding, which enforces the effect ofMICT00000110172.1in an allele-specific manner, and thus confers susceptibility to tumorigenesis. In summary, our results extend the repertoire of PDAC-associated lncRNAs that could act as a starting point for future functional explorations, and the identification of lncRNA‐based target therapy.