Epigenomic charting and functional annotation of risk loci in renal cell carcinoma.

TitleEpigenomic charting and functional annotation of risk loci in renal cell carcinoma.
Publication TypeJournal Article
Year of Publication2023
AuthorsNassar AH, Alaiwi SAbou, Baca SC, Adib E, Corona RI, Seo J-H, Fonseca MAS, Spisak S, Zarif TEl, Tisza V, Braun DA, Du H, He M, Flaifel A, Alchoueiry M, Denize T, Matar SG, Acosta A, Shukla S, Hou Y, Steinharter J, Bouchard G, Berchuck JE, O'Connor E, Bell C, Nuzzo PVitale, Lee G-SMary, Signoretti S, Hirsch MS, Pomerantz M, Henske E, Gusev A, Lawrenson K, Choueiri TK, Kwiatkowski DJ, Freedman ML
JournalNat Commun
Date Published2023 Jan 21
KeywordsCarcinoma, Renal Cell, Epigenomics, Forkhead Transcription Factors, Humans, Kidney Neoplasms, Oncogenes, Transcription Factors

While the mutational and transcriptional landscapes of renal cell carcinoma (RCC) are well-known, the epigenome is poorly understood. We characterize the epigenome of clear cell (ccRCC), papillary (pRCC), and chromophobe RCC (chRCC) by using ChIP-seq, ATAC-Seq, RNA-seq, and SNP arrays. We integrate 153 individual data sets from 42 patients and nominate 50 histology-specific master transcription factors (MTF) to define RCC histologic subtypes, including EPAS1 and ETS-1 in ccRCC, HNF1B in pRCC, and FOXI1 in chRCC. We confirm histology-specific MTFs via immunohistochemistry including a ccRCC-specific TF, BHLHE41. FOXI1 overexpression with knock-down of EPAS1 in the 786-O ccRCC cell line induces transcriptional upregulation of chRCC-specific genes, TFCP2L1, ATP6V0D2, KIT, and INSRR, implicating FOXI1 as a MTF for chRCC. Integrating RCC GWAS risk SNPs with H3K27ac ChIP-seq and ATAC-seq data reveals that risk-variants are significantly enriched in allelically-imbalanced peaks. This epigenomic atlas in primary human samples provides a resource for future investigation.

Alternate JournalNat Commun
PubMed ID36681680
PubMed Central IDPMC9867739
Grant ListT32 CA009172 / CA / NCI NIH HHS / United States
R01 CA251555 / CA / NCI NIH HHS / United States
P30 CA006516 / CA / NCI NIH HHS / United States
R01 CA227237 / CA / NCI NIH HHS / United States
P50 CA101942 / CA / NCI NIH HHS / United States
Related Faculty: 
Pier Nuzzo, Ph.D.

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