Pan-Cancer Analysis of Head-to-Head Gene Pairs in Terms of Transcriptional Activity, Co-expression and Regulation

Abstract

BackgroundHead-to-Head (H2H) gene pairs are regulated by bidirectional promoters and divergently transcribed from opposite DNA strands with transcription start sites (TSSs) separated within 1 kb. H2H organization is ancient and conserved, and H2H pairs tend to exhibit similar expression patterns. Although some H2H genes have been reported to be associated with disease and cancer, there is a lack of systematic studies on H2H organization in the scenario of cancer development.MethodsHuman H2H gene pairs were identified based on GENCODE hg19 and the functional relevance of H2H pairs was explored through function enrichment and semantic similarity analysis. To investigate the association between H2H organization and carcinogenesis, pan-cancer differential analysis of H2H genes about transcriptional activity, co-expression and transcriptional regulation by transcription factors and enhancers were performed based on data from The Cancer Genome Atlas. Cox proportional hazards regression model and log-rank test were used to determine the prognostic powers of H2H pairs.ResultsIn the present study, we first updated H2H genes from 1,447 to 3,150 pairs, from which the peak group with TSS distance of 1–100 was observed as expected in our previous work. It was found that housekeeping genes, mitochondrial-functional associated genes and cancer genes tend to be organized in H2H arrangement. Pan-cancer analysis indicates that H2H genes are transcriptionally active than random genes in both normal and cancer tissues, but H2H pairs display higher correlation in cancer than in normal. Particularly, housekeeping H2H pairs are differentially correlated much more significantly than non-housekeeping H2H pairs are. Some of differentially correlated H2H pairs were found to be associated with prognosis. The alteration of TF similarity seems to contribute to differential co-expression of H2H pairs during carcinogenesis; meanwhile remote enhancers also at least partly explain the differential co-expression and co-regulation of H2H pairs.ConclusionH2H pairs tend to show much stronger positive expression correlation in cancer than in normal due to differential regulation of bidirectional promoters. The study provides insights into the significance of H2H organization in carcinogenesis and the underlying dysfunctional regulation mechanisms. Those differentially correlated H2H pairs associated with survival have the potential to be prognostic biomarkers and therapeutic targets for cancer.

Identification and characterization of differentially co-expressed head-to-head gene pairs in pancreatic cancer

“…1646 protein coding H2H genes were identified, selecting genes which are on opposite strands to avoid counting adjacent gene pairs. This updated list of protein coding H2H gene pairs is a 38% increase from the most recent pan-cancer analysis of H2H pairs, which identified 1196 protein coding pairs (Chen et al ., 2021). Updates to genome annotation databases and TSS data can account for this increase.…”

“…As previous pan-cancer analyses of H2H genes have revealed that gene pairs have significantly altered co-expression matrices, it is quite possible that unique biomarkers could be found among differentially co-expressed H2H pairs (Chen et al ., 2021). H2H genes involving DNA repair and carcinogenesis genes being differentially co-expressed is also rather common, disrupting the expression coordination of these crucial genes.…”

SETD1A regulates transcriptional pause release of heme biosynthesis genes in leukemia

“…Genes for both DNA repair systems and mitochondrial respiration can be classified as H2H genes, which are regulated by bidirectional promoters. 25 Interestingly, 43% of DR genes are classified as H2H genes with another gene located on the opposite strand within 1 kb upstream from the TSS ( Figure 5B ). H2H pairs tend to show similar expression patterns because of the shared promoter activity, but DR H2H pairs showed divergent gene expression after dTAG-13 treatment ( Figures 5C and 5D ).…”

“…Thus, a synchronized regulation for these genes could be important for cell division with continuous cell cycling. 25 , 27 The pause release of RNAPII also has an important role in synchronous patterns of gene activation. 42 The evolution of the pause release system in H2H genes might have coincided with the molecular evolutions of the SETD1A-NELF axis to enable more precise and synchronized gene regulation in vertebrates.…”

Pan-Cancer Analysis Reveals the Prognostic Potential of the THAP9/THAP9-AS1 Sense–Antisense Gene Pair in Human Cancers

“…We used the RNA-seq HTSeq count dataset of 22 cancer and paired normal samples from TCGA. A pan-cancer analysis of head-to-head gene pairs [ 100 ] reported that these gene pairs show significantly stronger positive correlations in tumor compared to normal samples, regardless of tumor types. Moreover, bidirectional promoters are known to regulate the expression of many cancer-related genes such as BRCA1 and TP53 [ 101 , 102 ].…”