Introduction to Cotranscriptional RNA Splicing

Merkhofer, Evan; Hu, Peter; Johnson, Tracy

doi:10.1007/978-1-62703-980-2_6

Cited by 62 publications

(49 citation statements)

References 86 publications

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“…Splicing and polyadenylation are thought to take place while the RNA is still engaged with the chromatin (co-transcriptionally) [21], [22], [23], [24], [25], [26] and [27]; and the spliceosome attempts to recognize bona fide splice sites and presumably keep pace with RNAPII, which elongates at greater than 1000 bp/min [28], [29], [30] and [31]. Two hypotheses attempt to explain the mechanism of co-transcriptional splicing.…”

Section: Diversity Generated By Rna Splicingmentioning

confidence: 99%

“…The “recruitment model” for splicing states that factors involved in splicing and other processing events are recruited to the elongating RNAPII via the C-terminal domain (CTD) of the polymerase [26], [32] and [27]. The “kinetic model” for splicing suggests that the RNAPII elongation rate influences the efficiency of splicing such that slower elongation rates provide more time for splice junction recognition and spliceosome assembly, thus favoring efficient splicing [33], [25], [26] and [27]. Conversely, splicing may regulate the rate of transcription elongation through an “elongation checkpoint” that presumably prevents transcript release from the chromatin in the event of incomplete splicing [34] and [35].…”

Section: Diversity Generated By Rna Splicingmentioning

confidence: 99%

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Genome stability versus transcript diversity

2016

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Our genome is protected from the introduction of mutations by high fidelity replication and an extensive network of DNA damage response and repair mechanisms. However, the expression of our genome, via RNA and protein synthesis, allows for more diversity in translating genetic information. In addition, the splicing process has become less stringent over evolutionary time allowing for a substantial increase in the diversity of transcripts generated. The result is a diverse transcriptome and proteome, which harbor selective advantages over a more tightly regulated system. Here, we describe mechanisms in place that both safeguard the genome and promote translational diversity, with emphasis on post-transcriptional RNA processing.

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Section: Diversity Generated By Rna Splicingmentioning

confidence: 99%

Section: Diversity Generated By Rna Splicingmentioning

confidence: 99%

Genome stability versus transcript diversity

2016

View full text Add to dashboard Cite

show abstract

“…Such co-transcriptional splicing has been demonstrated in a number of different organisms and has been shown to play a role in coordinating both constitutive and alternative splicing [46]. It has been reported that by recruiting receptor co-regulators that can both control gene transcription and splicing, steroid hormones (in this case progesterone and estrogen) may coordinately control gene transcription and splicing decisions leading to alternatively spliced transcripts [47].…”

Section: Vitamin D and Rna Splicingmentioning

confidence: 99%

Vitamin D and alternative splicing of RNA

Zhou

Chun

Lisse

et al. 2015

The Journal of Steroid Biochemistry and Molecular Biology

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The active form of vitamin D (1α,25-dihydroxyvitamin D, 1,25(OH)2D) exerts its genomic effects via binding to a nuclear high-affinity vitamin D receptor (VDR). Recent deep sequencing analysis of VDR binding locations across the complete genome has significantly expanded our understanding of the actions of vitamin D and VDR on gene transcription. However, these studies have also promoted appreciation of the extra-transcriptional impact of vitamin D on gene expression. It is now clear that vitamin D interacts with the epigenome via effects on DNA methylation, histone acetylation, and microRNA generation to maintain normal biological functions. There is also increasing evidence that vitamin D can influence pre-mRNA constitutive splicing and alternative splicing, although the mechanism for this remains unclear. Pre-mRNA splicing has long been thought to be a post-transcription RNA processing event, but current data indicate that this occurs co-transcriptionally. Several steroid hormones have been recognized to coordinately control gene transcription and pre-mRNA splicing through the recruitment of nuclear receptor co-regulators that can both control gene transcription and splicing. The current review will discuss this concept with specific reference to vitamin D, and the potential role of heterogeneous nuclear ribonucleoprotein C (hnRNPC), a nuclear factor with an established function in RNA splicing. hnRNPC, has been shown to be involved in the VDR transcriptional complex as a vitamin D-response element-binding protein (VDRE-BP), and may act as a coupling factor linking VDR-directed gene transcription with RNA splicing. In this way hnRNPC may provide an additional mechanism for the fine-tuning of vitamin D-regulated target gene expression.

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“…The two most commonly utilized mechanisms for ASOs in therapeutic applications are 1) recruitment of RNaseH1 to the RNA/ASO hybrid and subsequent degradation of the RNA (Wu et al 2004a), and 2) correction of splicing defects that lead to disease when the ASO is designed to target splice junctions (Sazani et al 2002;Alter et al 2006). Because ASOs can modulate splicing, which occurs cotranscriptionally during the synthesis of RNA (Beyer et al 1981;Osheim et al 1985;Wu et al 1991;Merkhofer et al 2014), we reasoned ASOs could 5 possibly interfere with transcription itself. Therefore, we examined more closely whether ASOs only mediate RNA degradation or might also be involved in preventing their transcriptional synthesis.…”

Section: Introductionmentioning

confidence: 99%

An antisense oligonucleotide leads to suppressed transcriptional elongation ofHdac2and long-term memory enhancement

et al. 2019

Preprint

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ABSTRACTRepression of the memory suppressor gene histone deacetylase 2 (Hdac2) in mice elicits cognitive enhancement, and drugs that block HDAC2 catalytic activity are being investigated for treating disorders affecting memory. Currently available compounds that target HDAC2 are not specific to the HDAC2 isoform, and have short half-lives. Antisense oligonucleotides (ASOs) are a class of drugs that base pair with RNA targets and exhibit extremely long-lasting, specific inhibition relative to small molecule drugs. We utilized an ASO to reduce Hdac2 messenger RNA (mRNA) quantities, and explored its longevity, specificity, and mechanism of repression. A single injection of the Hdac2-targeted ASO in the central nervous system diminished Hdac2 mRNA levels for at least 4 months in the brain, and knockdown of this factor resulted in significant memory enhancement for 8 weeks in mice. RNA-seq analysis of brain tissues revealed that the ASO repression was specific to the Hdac2 isoform relative to other classical Hdac genes, and caused alterations in levels of other memory-associated mRNAs. In cultured neurons, we observed that the Hdac2-targeted ASO suppressed Hdac2 mRNA and an Hdac2 non-coding regulatory extra-coding RNA (ecRNA). The ASO not only triggered a reduction in mRNA levels, but also elicited direct transcriptional suppression of the Hdac2 gene through blocking RNA polymerase II elongation. These findings suggest transcriptional suppression of the target gene as a novel mechanism of action of ASOs, and opens up the possibility of using ASOs to achieve lasting gene silencing in the brain without altering the nucleotide sequence of a gene.

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Introduction to Cotranscriptional RNA Splicing

Cited by 62 publications

References 86 publications

Genome stability versus transcript diversity

Genome stability versus transcript diversity

Vitamin D and alternative splicing of RNA

An antisense oligonucleotide leads to suppressed transcriptional elongation ofHdac2and long-term memory enhancement

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