The dual lives of bidirectional promoters

Wakano, Clay; Byun, Jung S.; Di, Lijun; Gardner, Kevin

doi:10.1016/j.bbagrm.2012.02.006

Cited by 50 publications

(60 citation statements)

References 35 publications

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“…It has been reported that many cancer or DNA repair associated genes have bidirectional partner genes, and that tandem repeated ETS binding sites are frequently found in the 5'-upstream regions of both genes [98][99][100][101]. Therefore, expression of many DNA repair factor encoding genes is thought to be regulated by TFs that bind to GGAA motifs.…”

Section: Biological Relevance Of Bidirectional Transcriptionmentioning

confidence: 99%

Transcriptional Regulation of the Human Genes that Encode DNA Repair- and Mitochondrial Function-Associated Proteins

Uchiumi¹,

Larsen²,

Tanuma³

2015

Advances in DNA Repair

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Section: Biological Relevance Of Bidirectional Transcriptionmentioning

confidence: 99%

Transcriptional Regulation of the Human Genes that Encode DNA Repair- and Mitochondrial Function-Associated Proteins

Uchiumi¹,

Larsen²,

Tanuma³

2015

Advances in DNA Repair

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“…HOTAIR, on the other hand, acts in trans to repress the expression of genes in the HoxD gene cluster (53). It has been proposed that antisense lncRNAs transcribed from bidirectional promoters may be involved in the regulation of the associated sense transcripts (47,54). Such an arrangement may allow tighter transcriptional regulation.…”

Section: Discussionmentioning

confidence: 99%

“…We found that in chickens it corresponds to an alternatively spliced, polyadenylated, antisense lncRNA, leading us to propose that the TERT promoter is bidirectional. Bidirectional promoters have been found to be pervasive in mammalian genomes, with more than 10% of known proteincoding genes being transcribed from such promoters (45)(46)(47). In humans, many lncRNAs are transcribed from bidirectional promoters.…”

Section: Discussionmentioning

confidence: 99%

Avian Leukosis Virus Activation of an Antisense RNA Upstream of TERT in B-Cell Lymphomas

Nehyba

Malhotra

Winans

et al. 2016

J Virol

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Avian leukosis virus (ALV) induces tumors by integrating its proviral DNA into the chicken genome and altering the expression of nearby genes via strong promoter and enhancer elements. Viral integration sites that contribute to oncogenesis are selected in tumor cells. Deep-sequencing analysis of B-cell lymphoma DNA confirmed that the telomerase reverse transcriptase (TERT) gene promoter is a common ALV integration target. Twenty-six unique proviral integration sites were mapped between 46 and 3,552 nucleotides (nt) upstream of the TERT transcription start site, predominantly in the opposite transcriptional orientation to TERT. Transcriptome-sequencing (RNA-seq) analysis of normal bursa revealed a transcribed region upstream of TERT in the opposite orientation, suggesting the TERT promoter is bidirectional. This transcript appears to be an uncharacterized antisense RNA. We have previously shown that TERT expression is upregulated in tumors with integrations in the TERT promoter region. We now report that the viral promoter drives the expression of a chimeric transcript containing viral sequences spliced to exons 4 through 7 of this antisense RNA. Clonal expansion of cells with ALV integrations driving overexpression of the TERT antisense RNA suggest it may have a role in tumorigenesis. IMPORTANCEThe data suggest that ALV integrations in the TERT promoter region drive the overexpression of a novel antisense RNA and contribute to the development of lymphomas. Avian leukosis virus (ALV) is a simple retrovirus that does not carry a viral oncogene but induces tumors by insertional mutagenesis (1, 2). ALV typically induces B-cell lymphomas, but can also induce erythroblastomas, hemangiomas, and myeloid tumors (1-3). Proviral integration can upregulate the expression of nearby genes via strong enhancers and promoter elements in the viral long terminal repeat (LTR) sequences. An advantage of using ALV as an insertional-mutagenesis tool is its relatively random integration pattern, with only a slight preference for actively transcribed sites (4-6). A reduced integration bias allows us to map proviral integrations in many genomic locations and to observe the selection of integration sites with oncogenic potential. Previous studies have shown common integration sites in ALV-induced lymphomas in the MYC, MYB, BIC (miR 155 precursor), and telomerase reverse transcriptase (TERT) genes (6-10). Highthroughput sequencing revealed multiple integration sites in a series of rapid-onset B-cell lymphomas (6). The TERT promoter region was identified as the most clonally expanded of these integrations, suggesting this is an early event in tumorigenesis (6). Twenty-six unique integration sites were identified in the region in multiple independent tumors (6).Telomerase is a ribonucleoprotein complex that adds repeat sequences to chromosome ends. It contains a catalytic protein component, TERT, as well as a noncoding telomerase RNA template component (TERC). Elevated telomerase activity has been detected in more than 90% of all hum...

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“…The idea that co-transcription could entail co-functionality of paired gene products is supported by the observation that divergent PCG/PCG pairs in the human genome (around 10% of all PCGs) are enriched in specific functional categories, such as DNA repair and the regulation of cell cycle and metabolism. 51 As the annotated promoter region separating the TSSs of ncRNA-RB1 and RB1 is only 114 bp in size, we reasoned that the transcripts are likely to be co-expressed from a shared bidirectional promoter. Conceptually, the transcript pairs originating from relatively short bidirectional promoters should be regulated in a coordinated manner, as on nucleosome-free promoters the establishment of an active transcription environment on one TSS facilitates transcription initiation by polymerase II also at the divergent TSS.…”

Section: Discussionmentioning

confidence: 99%

A long non-coding RNA links calreticulin-mediated immunogenic cell removal to RB1 transcription

Huang

Rusakiewicz

et al. 2015

Oncogene

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A subset of promoters bidirectionally expresses long non-coding RNAs (ncRNAs) of unknown function and protein-coding genes (PCGs) in parallel. Here, we define a set of 1107 highly conserved human bidirectional promoters that mediate the linked expression of long ncRNAs and PCGs. Depletion of the long ncRNA expressed from the RB1 promoter, ncRNA-RB1, reveals regulatory effects different from the RB1-controlled transcriptional program. ncRNA-RB1 positively regulates the expression of calreticulin (CALR) that in response to certain therapeutic interventions can translocate from the endoplasmic reticulum to the cell surface, hence activating anticancer immune responses. Knockdown of ncRNA-RB1 in tumor cells reduced expression of CALR, impaired the translocation of the protein to the cell surface upon treatment with anthracylines and consequently inhibited the cellular uptake by macrophages. In conclusion, co-transcription of ncRNA-RB1 and RB1 provides a positive link between the expression of the two tumor suppressors RB1 and the immune-relevant CALR protein. This regulatory interplay exemplifies disease-relevant co-regulation of two distinct gene products, in which loss of expression of one oncosuppressor protein entails the abolition of additional tumorinhibitory mechanisms.

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The dual lives of bidirectional promoters

Cited by 50 publications

References 35 publications

Transcriptional Regulation of the Human Genes that Encode DNA Repair- and Mitochondrial Function-Associated Proteins

Transcriptional Regulation of the Human Genes that Encode DNA Repair- and Mitochondrial Function-Associated Proteins

Avian Leukosis Virus Activation of an Antisense RNA Upstream of TERT in B-Cell Lymphomas

A long non-coding RNA links calreticulin-mediated immunogenic cell removal to RB1 transcription

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