journal contribution
posted on 2023-03-31, 00:00 authored by Elinne Becket, Sameer Chopra, Christopher E. Duymich, Justin J. Lin, Jueng Soo You, Kurinji Pandiyan, Peter W. Nichols, Kimberly D. Siegmund, Jessica Charlet, Daniel J. Weisenberger, Peter A. Jones, Gangning Liang Supplementary Figure 1. Quantitation and location of epigenetic changes in all 6 patient samples. Supplementary Figure 2. Significant accessibility changes between 6 patients. Supplementary Figure 3. Accessibility changes shared in at least two patient samples, plotted in heatmaps, either losing accessibility (Groups a and e) or gaining accessibility (Groups d and f) with or without DNA methylation. Supplementary Figure 4. ChIP-seq analyses of Patient 5. Supplementary Figure 5. Validation of AcceSssIble data from each Group a, d, e, and f using locus-specific bisulfite sequencing. Supplementary Figure 6. Correlation plots of chromatin accessibility and DNA methylation changes vs. gene expression changes. Supplementary Figure 7. Epigenetically-regulated genes in the HIF1A-signaling pathway and VHL status in each ccRCC patient. Supplementary Figure 8. Example diagram of M.SssI treatment efficacy. Supplementary Table 1. List of loci with methylation-dependent accessibility changes that positively correlate with expression changes from TCGA RNA-seq data. Supplementary Table 2. List of loci with methylation-independent accessibility changes that positively correlate with expression changes from TCGA RNA-seq data. Supplementary Table 3. List of genes overlapping between epigenetically-regulated genes from our study, and commonly mutated genes in ccRCC from TCGA.
Funding
USC CTSI Pilot Funding Program
Glen and Wendy Miller/Inderbir Gill Kidney Cancer Research Program
AP Giannini Postdoctoral Research Fellowship Foundation
NIH Viral and Chemical Carcinogenesis Training
History
ARTICLE ABSTRACT
Alterations in chromatin accessibility independent of DNA methylation can affect cancer-related gene expression, but are often overlooked in conventional epigenomic profiling approaches. In this study, we describe a cost-effective and computationally simple assay called AcceSssIble to simultaneously interrogate DNA methylation and chromatin accessibility alterations in primary human clear cell renal cell carcinomas (ccRCC). Our study revealed significant perturbations to the ccRCC epigenome and identified gene expression changes that were specifically attributed to the chromatin accessibility status whether or not DNA methylation was involved. Compared with commonly mutated genes in ccRCC, such as the von Hippel-Lindau (VHL) tumor suppressor, the genes identified by AcceSssIble comprised distinct pathways and more frequently underwent epigenetic changes, suggesting that genetic and epigenetic alterations could be independent events in ccRCC. Specifically, we found unique DNA methylation–independent promoter accessibility alterations in pathways mimicking VHL deficiency. Overall, this study provides a novel approach for identifying new epigenetic-based therapeutic targets, previously undetectable by DNA methylation studies alone, that may complement current genetic-based treatment strategies. Cancer Res; 76(7); 1954–64. ©2016 AACR.
