Bidirectional promoters exhibit characteristic chromatin modification signature associated with transcription elongation in both sense and antisense directions

Abstract

BackgroundIn contrast to unidirectional promoters wherein antisense transcription results in short transcripts which are rapidly degraded, bidirectional promoters produce mature transcripts in both sense and antisense orientation. To understand the molecular mechanism of how productive bidirectional transcription is regulated, we focused on delineating the chromatin signature of bidirectional promoters.ResultsWe report generation and utility of a reporter system that enables simultaneous scoring of transcriptional activity in opposite directions. Testing of putative bidirectional promoters in this system demonstrates no measurable bias towards any one direction of transcription. We analyzed the NUP26L-PIH1D3 bidirectional gene pair during Retinoic acid mediated differentiation of embryonic carcinoma cells. In their native context, we observed that the chromatin landscape at and around the transcription regulatory region between the pair of bidirectional genes is modulated in concordance with transcriptional activity of each gene in the pair. We then extended this analysis to 974 bidirectional gene pairs in two different cell lines, H1 human embryonic stem cells and CD4 positive T cells using publicly available ChIP-Seq and RNA-Seq data. Bidirectional gene pairs were classified based on the intergenic distance separating the two TSS of the transcripts analyzed as well as the relative expression of each transcript in a bidirectional gene pair. We report that for the entire range of intergenic distance separating bidirectional genes, the expression profile of such genes (symmetric or asymmetric) matches the histone modification profile of marks associated with active transcription initiation and elongation.ConclusionsWe demonstrate unique distribution of histone modification marks that correlate robustly with the transcription status of genes regulated by bidirectional promoters. These findings strongly imply that occurrence of these marks might signal the transcription machinery to drive maturation of antisense transcription from the bidirectional promoters.Electronic supplementary materialThe online version of this article (10.1186/s12864-018-4697-7) contains supplementary material, which is available to authorized users.

LncRNA‐MAP3K4 regulates vascular inflammation through the p38 MAPK signaling pathway andcis‐modulation of MAP3K4

“…LncRNA transcription from a bidirectional promoter often impacts the expression of neighboring PCGs by modifying the local chromatin structure and affecting its accessibility. 40,90,91 By analyzing the ChIP-seq and ATAC-seq from the ENCODE 3 project ( Figure 5Q), we found that the histone modification markers such as H3K4me2, H3K4me3, H3K27ac, and H3K9ac exhibit bimodal enrichment around the overlapping promoter region of the lncRNA-MAP3K4/ MAP3K4 pair, as characteristic of bidirectional promoters. 40,43 In addition, ATAC-seq and Dnase I hypersensitivity (HS) show a signal peak around this promoter region, suggesting open and accessible chromatin.…”

“…Furthermore, histone modification markers mentioned above exhibited bimodal accumulation with a trough shape in the overlapping promoter region, which is characteristic of the bidirectional promoters region in ChIP-seq analysis. 40,43 DNase I HS was also enriched around this region, suggesting a chromatin structure modification, and ATAC-seq data showed open chromatin opening in this promoter region ( Figure 5Q). Collectively, consistent with other examples of lncRNA-mRNA pairs sharing a bidirectional promoter, 35,38,56 our experimental studies indicate that the overlapping promoter region of MAP3K4 and lncRNA-MAP3K4 is a bidirectional promoter, and our results confirm lncRNA-MAP3K4 regulates MAP3K4 expression in cis.…”

Unexplored regulatory sequences of divergently paired GLA and HNRNPH2 loci pertinent to Fabry disease in human kidney and skin cells: Presence of an active bidirectional promoter

“…Additional experimental studies using novel methods, including high-throughput assays ( 63 ) are required for the better understanding of the architecture and cis-regulatory elements of GLA and HNRNPH2 . Furthermore, investigation into the role of chromatin ( 64 ) on the transcriptional status of the two genes may be required. Another limitation to the present study is the lack of tissues or cells from patients with FD.…”

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

“…Indeed, some of bidirectional genes are often associated with functions in DNA repair, with the potential to participate in the development of cancer (Adachi & Lieber, 2002; Koyanagi et al, 2005; Yang, Koehly & Elnitski, 2007). Previous studies indicated that bidirectional gene pairs are associated with several genomic regulatory features such as CpG island methylation and histone modification (Adachi & Lieber, 2002; Jangid et al, 2018; Lin et al, 2007; Shu et al, 2006; Trinklein et al, 2004).…”