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Downstream Antisense Transcription Predicts Genomic Features That Define the Specific Chromatin Environment at Mammalian Promoters.

ABSTRACT: Antisense transcription is a prevalent feature at mammalian promoters. Previous studies have primarily focused on antisense transcription initiating upstream of genes. Here, we characterize promoter-proximal antisense transcription downstream of gene transcription starts sites in human breast cancer cells, investigating the genomic context of downstream antisense transcription. We find extensive correlations between antisense transcription and features associated with the chromatin environment at gene promoters. Antisense transcription downstream of promoters is widespread, with antisense transcription initiation observed within 2 kb of 28% of gene transcription start sites. Antisense transcription initiates between nucleosomes regularly positioned downstream of these promoters. The nucleosomes between gene and downstream antisense transcription start sites carry histone modifications associated with active promoters, such as H3K4me3 and H3K27ac. This region is bound by chromatin remodeling and histone modifying complexes including SWI/SNF subunits and HDACs, suggesting that antisense transcription or resulting RNA transcripts contribute to the creation and maintenance of a promoter-associated chromatin environment. Downstream antisense transcription overlays additional regulatory features, such as transcription factor binding, DNA accessibility, and the downstream edge of promoter-associated CpG islands. These features suggest an important role for antisense transcription in the regulation of gene expression and the maintenance of a promoter-associated chromatin environment.

SUBMITTER: Lavender CA

PROVIDER: S-EPMC4972320 | biostudies-literature | 2016 Aug

REPOSITORIES: biostudies-literature

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Downstream Antisense Transcription Predicts Genomic Features That Define the Specific Chromatin Environment at Mammalian Promoters.

Lavender Christopher A CA Cannady Kimberly R KR Hoffman Jackson A JA Trotter Kevin W KW Gilchrist Daniel A DA Bennett Brian D BD Burkholder Adam B AB Burd Craig J CJ Fargo David C DC Archer Trevor K TK

PLoS genetics 20160803 8

Antisense transcription is a prevalent feature at mammalian promoters. Previous studies have primarily focused on antisense transcription initiating upstream of genes. Here, we characterize promoter-proximal antisense transcription downstream of gene transcription starts sites in human breast cancer cells, investigating the genomic context of downstream antisense transcription. We find extensive correlations between antisense transcription and features associated with the chromatin environment a ...[more]

PMID: 27487356

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Project description:BACKGROUND:In 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. RESULTS:We 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. CONCLUSIONS:We 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.

Project description:We spliced the promoters of the human telomerase and human survivin genes (PhTERT and PhSurv, respectively) widely used for gene therapy and known to have the broadest cancer type spectrum of activity. Two head-to-tail constructs were obtained: the PhTERT-PhSurv and PhSurv-PhTERT tandems. The splicing caused quantitative and qualitative changes in the promoter features. In both constructs, only the promoter proximal to the transcribed gene retained its ability to initiate transcription, whereas the distal promoter was silent, the phenomenon never reported before. However, the distal promoter modulated the activity of the proximal one by increasing its strength and causing an appearance of additional transcription start sites. We suggested that this suppression might be due to the presence of Sp1 transcription factor binding sites in both promoters and Sp1-bridges between these sites. Such Sp1-bridges might convert the tandem promoter linear DNA into a stem-loop structure. If localized inside the formed loop, the distal promoter could lose its ability to initiate transcription. To test this hypothesis, we constructed two modified double promoters, where the proximal PhSurv promoter was replaced either by a shortened variant of the survivin promoter (PhSurv269) or by the mouse survivin promoter. Both PhSurv substitutes were considerably shorter than PhSurv and had different numbers and/or positions of Sp1 sites. In modified tandems, transcription was initiated from both promoters. We also prepared two mutant forms of the PhSurv-PhTERT tandem with two or four Sp1 sites removed from the distal "long" PhSurv promoter. In the first case, the distal PhSurv promoter remained silent, whereas the removal of four Sp1 binding sites restored its activity. In the majority of studied cancer cell lines the efficiency of transcription from the hTERT-(shortened hSurv269) promoter tandem was markedly higher than from each constituent promoter. In normal lung fibroblast cells, the tandem promoter activity was considerably lower.

Dataset Information

Downstream Antisense Transcription Predicts Genomic Features That Define the Specific Chromatin Environment at Mammalian Promoters.

Publications

Downstream Antisense Transcription Predicts Genomic Features That Define the Specific Chromatin Environment at Mammalian Promoters.

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