Scholarlink

<p>Most prostate cancer risk variants reside in noncoding DNA, but connecting germline alleles to lineage transcription factor (TF) programs has been challenging. We developed immunoprecipitation-coupled SNPs-seq (IP-SNPs-seq), enabling high-throughput, allele-specific, TF-resolved interrogation of candidate regulatory variants. Screening 903 prostate cancer–associated SNPs with androgen receptor (AR) immunoprecipitation, we identified multiple alleles with biased AR binding and convergent evidence from eQTL and ChIP-seq datasets. Among these, rs7600820 emerged as a functional enhancer variant: the risk G allele conferred stronger reporter activity, heightened AR responsiveness to dihydrotestosterone, and increased ODC1 expression; chromatin profiling and Hi-C revealed an active enhancer loop to the ODC1 promoter. ODC1 was consistently upregulated in primary and metastatic tumors across independent cohorts, associated with adverse clinicopathologic features, and required for prostate cancer cell proliferation. Gene-set enrichment analyses linked high ODC1 expression to MYC target signatures, positioning ODC1 as a clinically relevant, AR-regulated oncogenic node that integrates germline risk with core prostate cancer circuitry. IP-SNPs-seq thus provides a scalable route from association to mechanism, broadly applicable to diverse TFs and diseases, and nominates the AR–rs7600820–ODC1 axis as a potential biomarker and therapeutic vulnerability in androgen-driven prostate cancer.</p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

IP-SNPs-seq links noncoding risk alleles to lineage transcription factor programs in prostate cancer

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年12月8日

查看全文
  • Wenjie Xu,
  • Qixiang Zhang,
  • Lijuan Qiao,
  • Zixi Wang,
  • Tian Wang,
  • Dandan Dong,
  • Qin Zhang,
  • Liang Wang,
  • Gong-Hong Wei,
  • Peng Zhang

摘要

Most prostate cancer risk variants reside in noncoding DNA, but connecting germline alleles to lineage transcription factor (TF) programs has been challenging. We developed immunoprecipitation-coupled SNPs-seq (IP-SNPs-seq), enabling high-throughput, allele-specific, TF-resolved interrogation of candidate regulatory variants. Screening 903 prostate cancer–associated SNPs with androgen receptor (AR) immunoprecipitation, we identified multiple alleles with biased AR binding and convergent evidence from eQTL and ChIP-seq datasets. Among these, rs7600820 emerged as a functional enhancer variant: the risk G allele conferred stronger reporter activity, heightened AR responsiveness to dihydrotestosterone, and increased ODC1 expression; chromatin profiling and Hi-C revealed an active enhancer loop to the ODC1 promoter. ODC1 was consistently upregulated in primary and metastatic tumors across independent cohorts, associated with adverse clinicopathologic features, and required for prostate cancer cell proliferation. Gene-set enrichment analyses linked high ODC1 expression to MYC target signatures, positioning ODC1 as a clinically relevant, AR-regulated oncogenic node that integrates germline risk with core prostate cancer circuitry. IP-SNPs-seq thus provides a scalable route from association to mechanism, broadly applicable to diverse TFs and diseases, and nominates the AR–rs7600820–ODC1 axis as a potential biomarker and therapeutic vulnerability in androgen-driven prostate cancer.