肾系因子PAX8与ccRCC致癌因子HIF2A之间的染色质水平相互作用a,b, ccRCC细胞系(a)和非ccRCC细胞系(b)的CRISPR-Cas9功能丧失筛选结果汇总。敏感性评分,日志2在试验结束时,与试验开始时相比,每个基因的前三个耗尽sgRNAs(每个条件重复两次)的平均值。ccRCC依赖项显示为红色。CTRL,非目标控制的平均值。c, TCGA数据中癌症类型特异性ATAC-seq峰值与ccRCC细胞中PAX8和HNF1B耗尽后可达性降低的峰值之间的重叠。上轴,重叠比值比(黑色),95%置信区间。下轴,P值,单边费雪精确检验(红色)。d,通过RIME检测786-M1A细胞中PAX8-和hif2a相互作用蛋白的重叠。e,来自HIF2A和PAX8相互作用体的89个共享核蛋白之间物理连接的网络呈现。蛋白质名称在扩展数据图4a中提供。f,来自786-M1A和OS-LM1异种移植物(各3个肿瘤)的HIF2A和PAX8 ChIP-seq信号的热图,这些区域具有强烈的PAX8 - HIF2A共结合(红色)、主要的HIF2A结合(蓝色)和主要的PAX8结合(灰色)。 Top panels show the average signal within each of the three categories in the same colors. g, HIF2A and PAX8 co-bound genomic regions with reduced accessibility following PAX8 depletion. Median ATAC-seq signal from 786-M1A cells expressing a control RNAi construct (shRen, N = 6) or PAX8-targeting RNAi constructs (shPAX8, N = 6). Median HIF2A and PAX8 ChIP-seq signals from 786-M1A and OS-LM1 xenografts, three tumous each. Asterisk indicates a region of interest. h, Fraction of PAX8 peaks (red) in all high-confidence open chromatin regions (all) and HIF2A ChIP-seq peaks in 786-M1A and OS-LM1 xenograft tumors. Asterisk indicates P < 1.0 × 10−300,双侧Fisher精确检验。信贷:自然(2022)。DOI: 10.1038 / s41586 - 022 - 04809 - 8