Characterization of bidirectional gene pairs in The Cancer Genome Atlas (TCGA) dataset

The “bidirectional gene pair” indicates a particular head-to-head gene organization in which transcription start sites of two genes are located on opposite strands of genomic DNA within a region of one kb. Despite bidirectional gene pairs are well characterized, little is known about their expression profiles and regulation features in tumorigenesis. We used RNA-seq data from The Cancer Genome Atlas (TCGA) dataset for a systematic analysis of the expression profiles of bidirectional gene pairs in 13 cancer datasets. Gene pairs on the opposite strand with transcription end site distance within one kb or on the same strand with the distance of two genes between 1–10 kb and gene pairs comprising two randomly chosen genes were used as control gene pairs (CG1, CG2, and random). We identified and characterized up-/down-regulated genes by comparing the expression level between tumors and adjacent normal tissues in 13 TCGA datasets. There were no consistently significant difference in the percentage of up-/down-regulated genes between bidirectional and control/random genes in most of TCGA datasets. However, the percentage of bidirectional gene pairs comprising two up- or two down-regulated genes was significantly higher than gene pairs from CG1/2 in 12/11 analyzed TCGA datasets and the random gene pairs in all 13 TCGA datasets. Then we identified the methylation correlated bidirectional genes to explore the regulatory mechanism of bidirectional genes. Like the differentially expressed gene pairs, the bidirectional genes in a pair were significantly prone to be both hypo- or hyper-methylation correlated genes in 12/13 TCGA datasets when comparing to the CG2/random gene pairs despite no significant difference between the percentages of hypo-/hyper-methylation correlated genes in bidirectional and CG2/random genes in most of TCGA datasets. Finally, we explored the correlation between bidirectional genes and patient’s survival, identifying prognostic bidirectional genes and prognostic bidirectional gene pairs in each TCGA dataset. Remarkably, we found a group of prognostic bidirectional gene pairs in which the combination of two protein coding genes with different expression level correlated with different survival prognosis in survival analysis for OS. The percentage of these gene pairs in bidirectional gene pair were significantly higher than the gene pairs in controls in COAD datasets and lower in none of 13 TCGA datasets.

Co-regulation and functional cooperativity of FOXM1 and RHNO1 bidirectional genes in ovarian cancer

SummaryWe report that the oncogenic transcription factorFOXM1is arranged in a head-to-head configuration withRHNO1, a gene involved in the ATR/CHK1-dependent DNA replication stress (DRS) response.FOXM1andRHNO1are both amplified and upregulated in high-grade serous ovarian cancer (HGSC).FOXM1andRHNO1expression are closely associated in normal and cancer tissues, including single cells, and a bidirectional promoter (F/R-BDP) mediates balanced expression. Targeting of FOXM1 and RHNO1 in HGSC cells using shRNA, CRISPR mutagenesis, or CRISPR interference directed to the F/R-BDP reduced DNA homologous recombination repair (HR) capacity, increased DNA damage, reduced clonogenic survival, and sensitized HGSC cells to the poly-ADP ribosylase inhibitor (PARPi) olaparib. Thus, there is functional cooperativity between FOXM1 and RHNO1 in cancer cells, and combinatorial targeting of this bidirectional gene pair may be a novel cancer therapeutic strategy. More broadly, our data provide evidence that bidirectional gene units function in human cancer.

Functions of the podocyte proteins nephrin and Neph3 and the transcriptional regulation of their genes

Nephrin and Neph-family proteins [Neph1–3 (nephrin-like 1–3)] belong to the immunoglobulin superfamily of cell-adhesion receptors and are expressed in the glomerular podocytes. Both nephrin and Neph-family members function in cell adhesion and signalling, and thus regulate the structure and function of podocytes and maintain normal glomerular ultrafiltration. The expression of nephrin and Neph3 is altered in human proteinuric diseases emphasizing the importance of studying the transcriptional regulation of the nephrin and Neph3 genes NPHS1 (nephrosis 1, congenital, Finnish type) and KIRREL2 (kin of IRRE-like 2) respectively. The nephrin and Neph3 genes form a bidirectional gene pair, and they share transcriptional regulatory mechanisms. In the present review, we summarize the current knowledge of the functions of nephrin and Neph-family proteins and transcription factors and agents that control nephrin and Neph3 gene expression.

Murine Cytomegalovirus Major Immediate-Early Enhancer Region Operating as a Genetic Switch in Bidirectional Gene Pair Transcription

ABSTRACT Enhancers are defined as DNA elements that increase transcription when placed in any orientation relative to a promoter. The major immediate-early (MIE) enhancer region of murine cytomegalovirus is flanked by transcription units ie1/3 and ie2, which are transcribed in opposite directions. We have addressed the fundamental mechanistic question of whether the enhancer synchronizes transcription of the bidirectional gene pair (synchronizer model) or whether it operates as a genetic switch, enhancing transcription of either gene in a stochastic alternation (switch model). Clonal analysis of cytokine-triggered, transcription factor-mediated MIE gene expression from latent viral genomes provided evidence in support of the switch model.