Rxivist combines preprints from bioRxiv with data from Twitter to help you find the papers being discussed in your field. Currently indexing 62,502 bioRxiv papers from 277,505 authors.
Allelic imbalance reveals widespread germline-somatic regulatory differences and prioritizes risk loci in Renal Cell Carcinoma
Andre P Fay,
Kevin C Vavra,
Toni K Choueiri,
Matthew L Freedman
Posted 08 May 2019
bioRxiv DOI: 10.1101/631150
Posted 08 May 2019
Determining the function of non-coding regulatory variants in cancer is a key challenge transcriptional biology. We investigated genetic (germline and somatic) determinants of regulatory mechanisms in renal cell carcinoma (RCC) using H3K27ac ChIP-seq data in 10 matched tumor/normal samples and RNA-seq data from 496/66 tumor/normal samples from The Cancer Genome Atlas (TCGA). Unsupervised clustering of H3K27ac activity cleanly separated tumor from normal individuals, highlighting extensive epigenetic reprogramming during transformation. We developed a novel method to test each chromatin feature for evidence of an allele-specific quantitative trait locus (asQTL) and evaluate tumor/normal differences in allele-specificity (d-asQTLs) while modelling local structural variation and read overdispersion. At an FDR of 5%, we identified 1,356 unique asQTL chromatin peaks in normal tissues; 2,868 in tumors; and 1,054 d-asQTLs (primarily imbalanced in tumor). The d-asQTL peaks were significantly enriched for RCC genome-wide association study (GWAS) heritability (32x, P=1.8x10-3) , more so than any other functional feature including all H3K27ac peaks (12x), super-enhancers (5x), and asQTL genes (4x). Intersection of asQTLs with RCC GWAS loci identified putative functional features for 6/17 known loci including tumor-specific activity at SCARB1, a cholesterol metabolism mediator, which has recently been implicated in RCC progression. We validated the asQTL variant through CRISPR interference (CRISPRi) and demonstrated a concomitant allelic effect on the overlapping enhancer and on downstream SCARB1 expression. Knockdowns of master transcription factors (TFs) involved in the hypoxia pathway altered the expression of SCARB1 in a kidney cancer cell line, consistent with a variant-TF interaction. Genome-wide, d-asQTLs were significantly enriched for tumor-specific binding of hypoxic transcription factors, implicating a more general mechanism for polygenic germline-somatic interaction.
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