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Genome-wide analysis of enhancer RNA in gene regulation across 12 mouse tissues.

Cheng JH, Pan DZ, Tsai ZT, Tsai HK - Sci Rep (2015)

Bottom Line: This result implies eRNA transcription indicates a state of enhancer that further increases gene expression.We further found a large number of eRNAs contain regions in which sequences and secondary structures are similar to microRNAs.Collectively, our results provide speculation that eRNAs may be associated with the selective activation of enhancer target genes.

View Article: PubMed Central - PubMed

Affiliation: Institute of Information Science, Academia Sinica, 128 Academia Road, Section 2, Nankang, Taipei 115, Taiwan.

ABSTRACT
Enhancers play a crucial role in gene regulation but the participation of enhancer transcripts (i.e. enhancer RNA, eRNAs) in regulatory systems remains unclear. We provide a computational analysis on eRNAs using genome-wide data across 12 mouse tissues. The expression of genes targeted by transcribing enhancer is positively correlated with eRNA expression and significantly higher than expression of genes targeted by non-transcribing enhancers. This result implies eRNA transcription indicates a state of enhancer that further increases gene expression. This state of enhancer is tissue-specific, as the same enhancer differentially transcribes eRNAs across tissues. Therefore, the presence of eRNAs describes a tissue-specific state of enhancer that is generally associated with higher expressed target genes, surmising as to whether eRNAs have gene activation potential. We further found a large number of eRNAs contain regions in which sequences and secondary structures are similar to microRNAs. Interestingly, an increasing number of recent studies hypothesize that microRNAs may switch from their general repressive role to an activating role when targeting promoter sequences. Collectively, our results provide speculation that eRNAs may be associated with the selective activation of enhancer target genes.

No MeSH data available.


Proportions of number of EneRNA and Enno-eRNA.Red denotes the percentage of enhancers transcribing eRNAs. Blue denotes those not transcribing eRNAs. The black line represents the 50% cutoff. The number of enhancers with and without eRNAs is listed to the left of the bar graph. The number of eRNAs is listed to the right of the bar graph.
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f1: Proportions of number of EneRNA and Enno-eRNA.Red denotes the percentage of enhancers transcribing eRNAs. Blue denotes those not transcribing eRNAs. The black line represents the 50% cutoff. The number of enhancers with and without eRNAs is listed to the left of the bar graph. The number of eRNAs is listed to the right of the bar graph.

Mentions: To investigate if eRNAs are globally associated with enhancer-regulated transcription, we first examined the prevalence of enhancer transcription. Although previous studies have highlighted that transcription at enhancers is widespread614, the existence of non-transcribing active enhancers111415 are often neglected. We hence conducted a genome-wide and cross-tissue analysis to determine enhancers that transcribe eRNAs. The enhancers of 12 tissues were obtained from Shen et al.26. Shen et al. identified enhancers by signals of histone markers and coactivators, and enhancer target genes by correlating the signals of histone markers and RNA polymerase II. A subset of their data is verified with luciferase assays, 3C and Hi-C experiments. The eRNAs are RNA-seq contigs obtained from ENCODE14, where they assembled contigs from contiguous regions covered by uniquely aligned reads. Following the eRNA determination method by ENCODE14, intergenic enhancers that contain the 5′ start of a RNA-seq contig are considered as an enhancer transcribing eRNA (EneRNA) and the contig as an eRNA. Conversely, an enhancer not-transcribing eRNA (Enno-eRNA) is defined as an intergenic enhancers without a RNA-seq contig. Note that Enno-eRNA do not refer to transcriptionally silent enhancers, and these regions may contain lowly expressed RNA transcripts that could not be assembled or are undetectable by current technology. We identified between 2000 to 4000 EneRNA for each of the 12 tissues. Among the examined tissues, at least 1/3 (1709 EneRNA, liver) of the intergenic enhancers transcribe eRNAs (Fig. 1). Conversely, at least 1/5 (7317 Enno-eRNA, placenta) of the enhancers do not transcribe eRNAs. The results verify that transcription at enhancers is indeed prevalent, but non-transcribing enhancers still exist in non-negligible proportions. Even with numerous experimental confirmations to support these enhancers are bona fide26, we still discovered substantial portions of these enhancers do not transcribe eRNAs. A likely explanation for this discovery is that enhancers might exist in two states as distinguished by the presence of eRNAs. It hence draws attention to whether the presence of eRNAs at enhancers would correspond to any transcriptional differences in enhancer-regulated transcription.


Genome-wide analysis of enhancer RNA in gene regulation across 12 mouse tissues.

Cheng JH, Pan DZ, Tsai ZT, Tsai HK - Sci Rep (2015)

Proportions of number of EneRNA and Enno-eRNA.Red denotes the percentage of enhancers transcribing eRNAs. Blue denotes those not transcribing eRNAs. The black line represents the 50% cutoff. The number of enhancers with and without eRNAs is listed to the left of the bar graph. The number of eRNAs is listed to the right of the bar graph.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4518263&req=5

f1: Proportions of number of EneRNA and Enno-eRNA.Red denotes the percentage of enhancers transcribing eRNAs. Blue denotes those not transcribing eRNAs. The black line represents the 50% cutoff. The number of enhancers with and without eRNAs is listed to the left of the bar graph. The number of eRNAs is listed to the right of the bar graph.
Mentions: To investigate if eRNAs are globally associated with enhancer-regulated transcription, we first examined the prevalence of enhancer transcription. Although previous studies have highlighted that transcription at enhancers is widespread614, the existence of non-transcribing active enhancers111415 are often neglected. We hence conducted a genome-wide and cross-tissue analysis to determine enhancers that transcribe eRNAs. The enhancers of 12 tissues were obtained from Shen et al.26. Shen et al. identified enhancers by signals of histone markers and coactivators, and enhancer target genes by correlating the signals of histone markers and RNA polymerase II. A subset of their data is verified with luciferase assays, 3C and Hi-C experiments. The eRNAs are RNA-seq contigs obtained from ENCODE14, where they assembled contigs from contiguous regions covered by uniquely aligned reads. Following the eRNA determination method by ENCODE14, intergenic enhancers that contain the 5′ start of a RNA-seq contig are considered as an enhancer transcribing eRNA (EneRNA) and the contig as an eRNA. Conversely, an enhancer not-transcribing eRNA (Enno-eRNA) is defined as an intergenic enhancers without a RNA-seq contig. Note that Enno-eRNA do not refer to transcriptionally silent enhancers, and these regions may contain lowly expressed RNA transcripts that could not be assembled or are undetectable by current technology. We identified between 2000 to 4000 EneRNA for each of the 12 tissues. Among the examined tissues, at least 1/3 (1709 EneRNA, liver) of the intergenic enhancers transcribe eRNAs (Fig. 1). Conversely, at least 1/5 (7317 Enno-eRNA, placenta) of the enhancers do not transcribe eRNAs. The results verify that transcription at enhancers is indeed prevalent, but non-transcribing enhancers still exist in non-negligible proportions. Even with numerous experimental confirmations to support these enhancers are bona fide26, we still discovered substantial portions of these enhancers do not transcribe eRNAs. A likely explanation for this discovery is that enhancers might exist in two states as distinguished by the presence of eRNAs. It hence draws attention to whether the presence of eRNAs at enhancers would correspond to any transcriptional differences in enhancer-regulated transcription.

Bottom Line: This result implies eRNA transcription indicates a state of enhancer that further increases gene expression.We further found a large number of eRNAs contain regions in which sequences and secondary structures are similar to microRNAs.Collectively, our results provide speculation that eRNAs may be associated with the selective activation of enhancer target genes.

View Article: PubMed Central - PubMed

Affiliation: Institute of Information Science, Academia Sinica, 128 Academia Road, Section 2, Nankang, Taipei 115, Taiwan.

ABSTRACT
Enhancers play a crucial role in gene regulation but the participation of enhancer transcripts (i.e. enhancer RNA, eRNAs) in regulatory systems remains unclear. We provide a computational analysis on eRNAs using genome-wide data across 12 mouse tissues. The expression of genes targeted by transcribing enhancer is positively correlated with eRNA expression and significantly higher than expression of genes targeted by non-transcribing enhancers. This result implies eRNA transcription indicates a state of enhancer that further increases gene expression. This state of enhancer is tissue-specific, as the same enhancer differentially transcribes eRNAs across tissues. Therefore, the presence of eRNAs describes a tissue-specific state of enhancer that is generally associated with higher expressed target genes, surmising as to whether eRNAs have gene activation potential. We further found a large number of eRNAs contain regions in which sequences and secondary structures are similar to microRNAs. Interestingly, an increasing number of recent studies hypothesize that microRNAs may switch from their general repressive role to an activating role when targeting promoter sequences. Collectively, our results provide speculation that eRNAs may be associated with the selective activation of enhancer target genes.

No MeSH data available.