Leveraging the Epigenomic Landscape to identify Histology-Specific Master transcription factors and to functionally annotate risk loci in renal cell carcinoma

We performed histone (ChIP-seq, the Assay for Transposase-Accessible Chromatin using sequencing (ATAC-seq), and RNA sequencing (RNA-seq) on 42 fresh frozen RCC tumor samples (24 ccRCC, 6 pRCC, 12 chRCC). We integrated 153 unique data sets to gain a holistic view of gene regulation in RCC subtypes and 50 candidate histology-specific master transcription factors (TF) to define RCC histologic subtypes. We also integrated RCC GWAS risk SNPs with H3K27ac ChIP-seq and ATAC-seq data and revealed that risk variants were significantly enriched in allelically imbalanced peaks We performed histone ChIP-seq, ATAC-seq, and RNA sequencing (RNA-seq) to annoate the epigenetic landscape then untegrate that data to nominate candidate master TFs important to maintain cellular identity. We manipulated the expression of two of these candidate TFs and evaluated RNA expression as a readout. We also GWAS risk loci with epigenetically marked peaks. This submission corresponds to ChIP-seq component of study. The RNA-seq samples were included on Dec 13, 2022.

本研究对42例新鲜冰冻肾细胞癌（Renal Cell Carcinoma, RCC）肿瘤样本实施了组蛋白染色质免疫共沉淀测序（Chromatin Immunoprecipitation sequencing, ChIP-seq）、转座酶可及性染色质测序测定（Assay for Transposase-Accessible Chromatin using sequencing, ATAC-seq）及RNA测序（RNA-seq），样本包含24例透明细胞肾细胞癌（clear cell RCC, ccRCC）、6例乳头状肾细胞癌（papillary RCC, pRCC）与12例嫌色细胞肾细胞癌（chromophobe RCC, chRCC）。我们整合了153组独立数据集，以全面阐释RCC亚型的基因调控机制，并遴选出50种组织学特异性候选主转录因子（Transcription Factor, TF），用于界定RCC的组织学亚型。本研究同时将RCC全基因组关联研究（Genome-Wide Association Study, GWAS）风险单核苷酸多态性（Single Nucleotide Polymorphisms, SNPs）数据与组蛋白H3赖氨酸27乙酰化（H3K27ac）ChIP-seq及ATAC-seq数据进行整合，发现风险变异在等位基因失衡峰中显著富集。我们通过组蛋白ChIP-seq、ATAC-seq及RNA-seq对表观遗传图谱进行注释，并整合上述数据以筛选出对维持细胞身份至关重要的候选主转录因子。我们对其中两种候选TF的表达进行了干预，并以RNA表达量作为检测读数开展评估。此外，我们还将GWAS风险位点与携带表观遗传标记的峰区域进行了整合分析。本次提交对应本研究的ChIP-seq部分。RNA-seq样本于2022年12月13日被纳入本数据集。