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Pooled CRISPR-Cas9失功能筛查结果。敏感性评分,日志2每个基因中消耗最多的三个sgRNAs的平均值,每个条件重复两次,在试验结束时与试验开始时进行比较。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峰与ccRCC细胞中PAX8和HNF1B耗尽后可及性降低的ATAC-seq峰重叠。上轴,重叠优势比(黑色),95%置信区间。下轴,P值,单侧Fisher确切检验(红色)。d,通过RIME测定786-M1A细胞中PAX8-和hif2a互作蛋白之间的重叠。e, HIF2A和PAX8互作体中89个共享核蛋白之间物理连接的网络表达。蛋白质名称在扩展数据图4a中提供。f,来自786-M1A和OS-LM1异种移植瘤(各3个肿瘤)的HIF2A和PAX8 ChIP-seq信号的热图,跨越PAX8 - HIF2A强联合结合区域(红色),主要HIF2A结合区域(蓝色)和主要PAX8结合区域(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,双面Fisher确切检验。信贷:自然(2022)。DOI: 10.1038 / s41586 - 022 - 04809 - 8