Intron DNA Sequences Can Be More Important Than the Proximal Promoter in Determining the Site of Transcript Initiation

Gallegos, Jenna E.; Rose, Alan B.

doi:10.1105/tpc.17.00020

Cited by 63 publications

(69 citation statements)

References 51 publications

(88 reference statements)

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“…Effects on antisense transcription in these mutant cell lines mirrored those observed for sense transcription ( Figure 3C), suggesting that inclusion of the new exon enhances transcription from the upstream promoter in both directions. This pattern is distinct from some observations of intron-mediated enhancement in which sense-oriented introns specifically inhibited antisense transcription (Agarwal and Ansari, 2016), but is consistent with reported impacts on transcription initiation resulting from changes in the position of an intron in a reporter gene (Gallegos and Rose, 2017).…”

Section: Manipulation Of Exon Splicing Impacts Upstream Transcriptionsupporting

confidence: 77%

Exon-mediated activation of transcription starts

Fiszbein

Krick

Burge

2019

Preprint

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The processing of transcripts from mammalian genes often occurs near in time and space to their transcription. Here we describe a phenomenon we call exon-mediated activation of transcription starts (EMATS) that affects thousands of mammalian genes in which the splicing of internal exons impacts the spectrum of promoters used and expression level of the host gene. We observed that evolutionary gain of new internal exons is associated with gain of new TSSs nearby and increased gene expression. Inhibiting exon splicing reduced transcription from nearby promoters. Conversely, creation of new splice sites and enable splicing of new exons activated transcription from cryptic promoters. The strongest effects were associated with weak promoters located proximal and upstream of efficiently spliced exons. Together, our findings support a model in which splicing factors recruit transcription machinery locally to influence TSS choice, and identify exon gain, loss and regulatory change as major contributors to the evolution of alternative promoters and altered gene expression in mammals.

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Section: Manipulation Of Exon Splicing Impacts Upstream Transcriptionsupporting

confidence: 77%

Exon-mediated activation of transcription starts

Fiszbein

Krick

Burge

2019

Preprint

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“…In genomes of animals, plants, fungi, and protists, intron positions could be conserved throughout prolonged evolutionary times, suggesting their involvement in gene expression and regulation, including mRNA processing (46)(47)(48). Numerous studies in animals and plants have emphasized that introns may carry functional cis-acting elements affecting gene expression even in the absence of promoter sequences (49)(50)(51)(52)(53). Recently, it was shown that nucleosomes preferentially occupy exons rather than introns, and this phenomenon seems to be interconnected with specific histone modifications favoring gene expression (54-56).…”

Section: Discussionmentioning

confidence: 99%

Insulator proteins contribute to expression of gene loci repositioned into heterochromatin in the course ofDrosophilaevolution

Rezvykh

et al. 2019

Preprint

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1 2 3 4 5 7 8of Drosophila melanogaster. Interestingly, genes embedded in pericentric heterochromatin of D. melanogaster may occupy different genomic loci, euchromatic or heterochromatic, due to repositioning in the course of evolution of Drosophila species. By surveying factors that contribute to the normal functioning of the relocated genes in distant Drosophila species, i.e. D. melanogaster and D. virilis, we identify certain insulator proteins (e.g.BEAF-32) that facilitate the expression of heterochromatic genes in spite of the repressive environment.Despite the repressive environment, dozens of essential genes were identified in the pericentric heterochromatin of D. melanogaster (13)(14)(15)(16). Interestingly, genes embedded in pericentric heterochromatin in D. melanogaster may occupy distinct genomic loci, euchromatic and heterochromatic, in other Drosophila species (17). For instance, two adjacent genes RpL15 and Dbp80 located in the pericentric region of chromosome 3L in D. melanogaster reside in a euchromatic region in D. pseudoobscura (18). A similar pattern was demonstrated for genes light and Yeti located in pericentric regions in D. melanogaster, while in D. virilis they are found within euchromatin on the same chromosomal elements (19,20). Recently, it was shown that most of the pericentric genes found at both arms of chromosome 2 of D. melanogaster are located in euchromatic loci in the D. virilis genome (21). However, although repositioning of genes between euchromatin and heterochromatin during genome evolution is not unusual in the Drosophilidae lineage, the "immunity" of heterochromatic genes to the transcriptionally repressive environment remains paradoxical and unexplained. Thus, it is not clear whether these loci have undergone adaptation to heterochromatic environment or had some intrinsic properties permitting local adaptation.Previously, it was shown that molecular organization of promoter regions is largely conserved between heterochromatic and euchromatic genes, indicating that adaptation to heterochromatin probably does not require major changes in regulatory sequences (20). However, expression of heterochromatic genes requires the methylated H3K9 mark (22,23), and the ability to repositioning during evolution is a characteristic feature of gene clusters that show close association with HP1a protein (21).Chromatin insulator elements and associated proteins were originally defined by their ability to protect transgenes from PEV, exerting a block to cis spreading of a chromatin state (24, 25). To date, a set of insulators have been identified in Drosophila, including BEAF-32 (Boundary element associated factor of 32 kDa), dCTCF (Drosophila homolog of CTCF), Su(Hw) (Suppressor of hairy wing), Zw5 (Zeste-white-5), GAF (GAGA factor) and recently expression of heterochromatic genes and make them predisposed for evolutionary repositioning into transcriptionally repressive genomic environments. Results Evolutionary repositioning of Myb and Ranbp16 genes between euchromatin and heterochromatin...

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“…The most thoroughly analyzed IME intron is the first intron from the Arabidopsis UBQ10 gene. This intron increases mRNA accumulation only when located downstream of the TSS, and can stimulate expression from at least 550 nt from the TSS but not 1,100 nt or more[20,21]. Remarkably, deleting a 300 nt region of the proximal promoter that contains all known TSSs does not diminish the expression of constructs containing this intron [21].…”

Section: Introductionmentioning

confidence: 99%

“…This intron increases mRNA accumulation only when located downstream of the TSS, and can stimulate expression from at least 550 nt from the TSS but not 1,100 nt or more[20,21]. Remarkably, deleting a 300 nt region of the proximal promoter that contains all known TSSs does not diminish the expression of constructs containing this intron [21]. Transcription in these promoter-deleted constructs initiates in normally untranscribed sequences the same distance upstream of the intron as when the promoter is intact.…”

Section: Introductionmentioning

confidence: 99%

“…Rearranging nucleotides to create 6 or 11 copies of this motif converted a non-stimulating intron from the COR15a gene in Arabidopsis into one that boosts mRNA accumulation 14- or 24-fold, respectively [32]. Introns containing this motif behave similarly to the UBQ10 intron in that they increase mRNA accumulation even in the absence of the proximal promoter [21], suggesting that the sequence TTNGATYTG is sufficient for IME.…”

Section: Introductionmentioning

confidence: 99%

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Intron-mediated enhancement is not limited to introns

Gallegos

Rose

2018

Preprint

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Certain introns strongly increase mRNA accumulation by a poorly understood mechanism known as Intron-Mediated Enhancement (IME). Introns that boost expression by IME have no effect when located upstream of or more than ~1 Kb downstream from the start of transcription. The sequence TTNGATYTG, which is over-represented in promoter-proximal introns in Arabidopsis thaliana, can convert a non-stimulating intron into one that strongly increases mRNA accumulation. We tested the ability of an intron containing this motif to stimulate expression from different locations and found that it had the same positional requirements as naturally occurring IME introns. The motif also stimulated gene expression from within the 5’-UTR and coding sequences of an intronless construct. Furthermore, the 5’-UTR of another gene increased expression when inserted into an otherwise non-stimulating intron in coding sequences. These results demonstrate that splicing is not required for intron-mediated enhancement, and suggest that other sequences downstream of the transcription start site in addition to introns may stimulate expression by a similar mechanism.

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Intron DNA Sequences Can Be More Important Than the Proximal Promoter in Determining the Site of Transcript Initiation

Cited by 63 publications

References 51 publications

Exon-mediated activation of transcription starts

Exon-mediated activation of transcription starts

Insulator proteins contribute to expression of gene loci repositioned into heterochromatin in the course ofDrosophilaevolution

Intron-mediated enhancement is not limited to introns

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