Genome-wide profiling in colorectal cancer identifies PHF19 and TBC1D16 as oncogenic super enhancers

Abstract

Colorectal cancer is one of the most common cancers in the world. Although genomic mutations and single nucleotide polymorphisms have been extensively studied, the epigenomic status in colorectal cancer patient tissues remains elusive. Here, together with genomic and transcriptomic analysis, we use ChIP-Seq to profile active enhancers at the genome wide level in colorectal cancer paired patient tissues (tumor and adjacent tissues from the same patients). In total, we sequence 73 pairs of colorectal cancer tissues and generate 147 H3K27ac ChIP-Seq, 144 RNA-Seq, 147 whole genome sequencing and 86 H3K4me3 ChIP-Seq samples. Our analysis identifies 5590 gain and 1100 lost variant enhancer loci in colorectal cancer, and 334 gain and 121 lost variant super enhancer loci. Multiple key transcription factors in colorectal cancer are predicted with motif analysis and core regulatory circuitry analysis. Further experiments verify the function of the super enhancers governing PHF19 and TBC1D16 in regulating colorectal cancer tumorigenesis, and KLF3 is identified as an oncogenic transcription factor in colorectal cancer. Taken together, our work provides an important epigenomic resource and functional factors for epigenetic studies in colorectal cancer.

Dissecting super-enhancer heterogeneity: time to re-examine cancer subtypes?

“…Summarizing the recent studies in multiple cancers [4][5][6][7][8][9][10][11] (Table 1), we distilled a bioinformatics workflow for the identification of subtype-specific SEs and putative targets with multi-omics characterizations, followed by SE-driven regulatory network inference to dissect cancer heterogeneity and elucidate the transcriptional circuitry underlying specific cancer subtypes (Figure 1).…”

Deciphering of Somatic Mutational Signatures of Cancer

“…Here, aiming to investigate dMRR and MSI-related signature in somatic mutations called by RNAseq, we tried to extend the application of GSGP to transcriptome MSs. Firstly, we collected RNAseq data from two CRC cohorts, Chonnam National University and Pusan National University CRC (CP-CRC) 45 and Zhongnan Hospital CRC (ZN-CRC) 46 , which contain 45 and 72 pairs of tumor-normal paired samples, respectively. When using a priori SBS signatures, we found that neither our identified SBS54 nor the widely established 7 dMMR-related signatures can distinguish between MSI and MSS samples (Fig.…”

“…Two CRC RNAseq datasets were downloaded from the Sequence Read Archive (SRA) (https://ncbi.nlm.nih.gov/sra) with accession number PRJNA748264 45 (n=45) and PRJNA658001 46 (n=72). SRA Toolkit (v3.0.0) was used to split the SRA files into pair-end FASTQ files.…”

Super-enhancer profiling identifies novel critical and targetable cancer survival gene LYL1 in pediatric acute myeloid leukemia

“…Super-enhancer was found to activate the Wnt/beta-catenin pathway and promotes the proliferation of liver cancer cells [ 17 ]. Oncogenic super-enhancers were also identified in colorectal cancer through genome-wide profiling [ 18 ]. In addition, super-enhancer was reported to play a role in glioma progression [ 19 ].…”

“…In hepatocellular carcinoma specimens, a live-specific super-enhancer drives lncRNA-DAW, leading to activation of the Wnt/beta-catenin pathway. Oncogenic super-enhancers were also identified in colorectal cancer through genome-wide profiling [ 18 ]. Via a genome-wide investigation of the enhancer distribution in colorectal cancer tissues, super-enhancer loci were identified.…”