A new study published in Nature has shed light on the epigenome of renal cell carcinomas (RCCs), the most common family of kidney tumours. Using cutting-edge techniques such as ChIP-seq, ATAC-Seq, RNA-seq, SNP arrays and immunohistochemistry, researchers have identified 50 histology-specific master transcription factors (TFs) that define RCC subtypes, including clear cell RCC (ccRCC), papillary RCC (pRCC), and chromophobe RCC (chRCC). The study provides a valuable resource for future investigation into RCCs.
RCCs account for 75% of all kidney tumour cases and have different outcomes and responses to treatments. Previous research has studied the genetic and molecular differences among RCC subtypes, but until now, the histone modifications and chromatin accessibility that control the transcriptional landscapes of RCCs have not been systematically explored.
Studying the chromatin landscape of Renal Cell Carcinomas
The study mapped the chromatin regulatory landscape of renal cell carcinomas by performing ChIP-seq (to study the interactions between proteins), ATAC-seq (for studying chromatin accessibility), and RNA-seq (for studying the transcripts of a genome) on 42 fresh frozen RCC tumour samples. The researchers identified 153,321 promoter-distal (enhancer) H3K27ac ChIP-Seq peaks across all the samples, most of which were common to two or more histologies. H3K27ac is a specific histone modification that is associated with active enhancers – regions of the genome that control the activity of genes. The study found that the H3K27ac landscape in chRCC was more distinct than pRCC or ccRCC.
The study aimed to identify candidate histology-specific master TFs that define the three subtypes of RCC. They used an integrative approach by combining different types of data, such as expression data of differentially expressed TFs across RCC histologic subtypes and TFs specific to RCC histologic subtypes relative to other cancer types. They identified more than 200 candidate TFs showing a histology-specific association. Through further analysis, they prioritized 50 candidate histology-specific master TFs, including FOXI1, TFCP2L1, and DMRT2 for chRCC; EPAS1, ETS1, BARX2, ZNF395 for ccRCC, and HNF1B and NR2F2 for pRCC. The researchers also used ChIP-seq to study allelic imbalance and identify which genetic changes are associated with RCC. They identified 10,605 regions of the genome where the activity of different alleles was imbalanced. They then looked at these regions in relation to known risk variants for RCC and found that the regions were highly enriched for RCC risk variants. They were also able to identify specific genetic changes that may contribute to RCC, such as rs4903064 and rs7132434.
Implications and future directions
This new study provides a valuable resource for future investigation into RCCs by characterizing their epigenomes and identifying key factors that drive the transcriptional states of these tumour subtypes. It has confirmed the expression and localization of these TFs through immunohistochemistry and has provided evidence that high BARX2 expression is significantly associated with poor overall survival in ccRCC patients. Overall, this research opens new doors for understanding the underlying biology of RCCs, and for developing new treatments for patients with these diseases.