TY - JOUR
T1 - Epigenomic charting and functional annotation of risk loci in renal cell carcinoma
AU - Nassar, Amin H.
AU - Abou Alaiwi, Sarah
AU - Baca, Sylvan C.
AU - Adib, Elio
AU - Corona, Rosario I.
AU - Seo, Ji Heui
AU - Fonseca, Marcos A.S.
AU - Spisak, Sandor
AU - El Zarif, Talal
AU - Tisza, Viktoria
AU - Braun, David A.
AU - Du, Heng
AU - He, Monica
AU - Flaifel, Abdallah
AU - Alchoueiry, Michel
AU - Denize, Thomas
AU - Matar, Sayed G.
AU - Acosta, Andres
AU - Shukla, Sachet
AU - Hou, Yue
AU - Steinharter, John
AU - Bouchard, Gabrielle
AU - Berchuck, Jacob E.
AU - O’Connor, Edward
AU - Bell, Connor
AU - Nuzzo, Pier Vitale
AU - Mary Lee, Gwo Shu
AU - Signoretti, Sabina
AU - Hirsch, Michelle S.
AU - Pomerantz, Mark
AU - Henske, Elizabeth
AU - Gusev, Alexander
AU - Lawrenson, Kate
AU - Choueiri, Toni K.
AU - Kwiatkowski, David J.
AU - Freedman, Matthew L.
N1 - Publisher Copyright:
© 2023, The Author(s).
PY - 2023/12
Y1 - 2023/12
N2 - 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.
AB - 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.
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U2 - 10.1038/s41467-023-35833-5
DO - 10.1038/s41467-023-35833-5
M3 - Article
C2 - 36681680
AN - SCOPUS:85146714235
SN - 2041-1723
VL - 14
JO - Nature communications
JF - Nature communications
IS - 1
M1 - 346
ER -