小柯机器人

美国丹纳-法伯癌症研究所Matthew L. Freedman和Alexander Gusev共同合作近期取得重要工作进展，他们研究发现染色质的遗传决定因素揭示了由环境依赖的基因调控所介导的前列腺癌风险。相关工作成果2022年9月7日在线发表于《自然—遗传学》杂志上。

为了应对这一挑战，研究人员开发了cistrome-wide关联研究（CWAS），这是一个用于识别与疾病相关的基因型和等位基因对染色质的特异性影响的框架。在前列腺癌中，CWAS确定了调节元件和雄激素受体结合位点，这些位点解释了98个已知前列腺癌风险基因座中的52个的关联，并发现了17个额外的风险基因座。CWAS涉及前列腺癌风险中的关键发育转录因子，由于环境依赖的相关基因调控，这些因子被基于eQTL的方法所忽视。研究人员通过实验验证了关联，并证明了CWAS对其他表观基因组数据集和表型的可扩展性，包括对前列腺癌治疗的反应。CWAS是研究通过影响转录调控而影响性状的变体的一个强大的、可解释的生物学范式。

据了解，许多遗传变异通过改变环境依赖的基因调控来影响疾病风险。这种变异很难使用目前将遗传变异与稳态基因表达水平联系起来的方法，（例如表达数量性状基因座（eQTLs））进行机理研究。

附：英文原文

Title: Genetic determinants of chromatin reveal prostate cancer risk mediated by context-dependent gene regulation

Author: Baca, Sylvan C., Singler, Cassandra, Zacharia, Soumya, Seo, Ji-Heui, Morova, Tunc, Hach, Faraz, Ding, Yi, Schwarz, Tommer, Huang, Chia-Chi Flora, Anderson, Jacob, Fay, Andr P., Kalita, Cynthia, Groha, Stefan, Pomerantz, Mark M., Wang, Victoria, Linder, Simon, Sweeney, Christopher J., Zwart, Wilbert, Lack, Nathan A., Pasaniuc, Bogdan, Takeda, David Y., Gusev, Alexander, Freedman, Matthew L.

Issue&Volume: 2022-09-07

Abstract: Many genetic variants affect disease risk by altering context-dependent gene regulation. Such variants are difficult to study mechanistically using current methods that link genetic variation to steady-state gene expression levels, such as expression quantitative trait loci (eQTLs). To address this challenge, we developed the cistrome-wide association study (CWAS), a framework for identifying genotypic and allele-specific effects on chromatin that are also associated with disease. In prostate cancer, CWAS identified regulatory elements and androgen receptor-binding sites that explained the association at 52 of 98 known prostate cancer risk loci and discovered 17 additional risk loci. CWAS implicated key developmental transcription factors in prostate cancer risk that are overlooked by eQTL-based approaches due to context-dependent gene regulation. We experimentally validated associations and demonstrated the extensibility of CWAS to additional epigenomic datasets and phenotypes, including response to prostate cancer treatment. CWAS is a powerful and biologically interpretable paradigm for studying variants that influence traits by affecting transcriptional regulation.

DOI: 10.1038/s41588-022-01168-y

Source: https://www.nature.com/articles/s41588-022-01168-y

Nature Genetics：《自然—遗传学》，创刊于1992年。隶属于施普林格·自然出版集团，最新IF：41.307
官方网址：https://www.nature.com/ng/
投稿链接：https://mts-ng.nature.com/cgi-bin/main.plex