Truncated ORF1 proteins can suppress LINE-1 retrotransposition in trans

Sokolowski, Mark J.; Chynces, May; deHaro, Dawn; Christian, Claiborne M.; Belancio, Victoria P.

doi:10.1093/nar/gkx211

Cited by 23 publications

(34 citation statements)

References 81 publications

(160 reference statements)

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“…Retroelements are nearly ubiquitious in extant genomes, and their expression is governed by disparate mechanisms, including expression of truncated ORFs and altered TSS utilization [ 74 , 75 ]. We are not aware of any precedent for Mediator affecting the balance between two promoters in the way we have reported here; future studies will be required to determine whether similar mechanisms apply in other cases in yeast or other organisms.…”

Section: Discussionmentioning

confidence: 99%

The Mediator co-activator complex regulates Ty1 retromobility by controlling the balance between Ty1i and Ty1 promoters

et al. 2018

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The Ty1 retrotransposons present in the genome of Saccharomyces cerevisiae belong to the large class of mobile genetic elements that replicate via an RNA intermediary and constitute a significant portion of most eukaryotic genomes. The retromobility of Ty1 is regulated by numerous host factors, including several subunits of the Mediator transcriptional co-activator complex. In spite of its known function in the nucleus, previous studies have implicated Mediator in the regulation of post-translational steps in Ty1 retromobility. To resolve this paradox, we systematically examined the effects of deleting non-essential Mediator subunits on the frequency of Ty1 retromobility and levels of retromobility intermediates. Our findings reveal that loss of distinct Mediator subunits alters Ty1 retromobility positively or negatively over a >10,000-fold range by regulating the ratio of an internal transcript, Ty1i, to the genomic Ty1 transcript. Ty1i RNA encodes a dominant negative inhibitor of Ty1 retromobility that blocks virus-like particle maturation and cDNA synthesis. These results resolve the conundrum of Mediator exerting sweeping control of Ty1 retromobility with only minor effects on the levels of Ty1 genomic RNA and the capsid protein, Gag. Since the majority of characterized intrinsic and extrinsic regulators of Ty1 retromobility do not appear to effect genomic Ty1 RNA levels, Mediator could play a central role in integrating signals that influence Ty1i expression to modulate retromobility.

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Section: Discussionmentioning

confidence: 99%

The Mediator co-activator complex regulates Ty1 retromobility by controlling the balance between Ty1i and Ty1 promoters

et al. 2018

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“…1996 ; Kulpa and Moran 2005 ; Goodier et al. 2007 ; Sokolowski et al. 2017 ) and a few present ORF0-like sequences ( Denli et al.…”

Section: Resultsmentioning

confidence: 99%

Novel Bioinformatics Approach Identifies Transcriptional Profiles of Lineage-Specific Transposable Elements at Distinct Loci in the Human Dorsolateral Prefrontal Cortex

Guffanti

Bartlett

Klengel

et al. 2018

Molecular Biology and Evolution

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Expression of transposable elements (TE) is transiently activated during human preimplantation embryogenesis in a developmental stage- and cell type-specific manner and TE-mediated epigenetic regulation is intrinsically wired in developmental genetic networks in human embryos and embryonic stem cells. However, there are no systematic studies devoted to a comprehensive analysis of the TE transcriptome in human adult organs and tissues, including human neural tissues. To investigate TE expression in the human Dorsolateral Prefrontal Cortex (DLPFC), we developed and validated a straightforward analytical approach to chart quantitative genome-wide expression profiles of all annotated TE loci based on unambiguous mapping of discrete TE-encoded transcripts using a de novo assembly strategy. To initially evaluate the potential regulatory impact of DLPFC-expressed TE, we adopted a comparative evolutionary genomics approach across humans, primates, and rodents to document conservation patterns, lineage-specificity, and colocalizations with transcription factor binding sites mapped within primate- and human-specific TE. We identified 654,665 transcripts expressed from 477,507 distinct loci of different TE classes and families, the majority of which appear to have originated from primate-specific sequences. We discovered 4,687 human-specific and transcriptionally active TEs in DLPFC, of which the prominent majority (80.2%) appears spliced. Our analyses revealed significant associations of DLPFC-expressed TE with primate- and human-specific transcription factor binding sites, suggesting potential cross-talks of concordant regulatory functions. We identified 1,689 TEs differentially expressed in the DLPFC of Schizophrenia patients, a majority of which is located within introns of 1,137 protein-coding genes. Our findings imply that identified DLPFC-expressed TEs may affect human brain structures and functions following different evolutionary trajectories. On one side, hundreds of thousands of TEs maintained a remarkably high conservation for ∼8 My of primates’ evolution, suggesting that they are likely conveying evolutionary-constrained primate-specific regulatory functions. In parallel, thousands of transcriptionally active human-specific TE loci emerged more recently, suggesting that they could be relevant for human-specific behavioral or cognitive functions.

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“…Retroelements are nearly ubiquitious in extant genomes, and their expression is governed by disparate mechanisms, including expression of truncated ORFs and altered TSS utilization [74, 75]. We are not aware of any precedent for Mediator regulating the balance between two promoters in the way we have reported here; future studies will be required to determine whether similar mechanisms apply in other cases in yeast or other organisms.…”

Section: Discussionmentioning

confidence: 96%

The Mediator co-activator complex regulates Ty1 retromobility by controlling the balance between Ty1i and Ty1 promoters

Salinero

Knoll

Zhu

et al. 2017

Preprint

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4The Ty1 retrotransposons present in the genome of Saccharomyces cerevisiae belong to the large class 3 5 of mobile genetic elements that replicate via an RNA intermediary and constitute a significant portion of 3 6 most eukaryotic genomes. The retromobility of Ty1 is regulated by numerous host factors, including 3 7 several subunits of the Mediator transcriptional co-activator complex. In spite of its known function in 3 8 the nucleus, previous studies have implicated Mediator in the regulation of post-translational steps in 3 9 Ty1 retromobility. To resolve this paradox, we systematically examined the effects of deleting non-4 0 essential Mediator subunits on the frequency of Ty1 retromobility and levels of retromobility 4 1 intermediates. Our findings reveal that loss of distinct Mediator subunits alters Ty1 retromobility 4 2 positively or negatively over a >10,000-fold range by regulating the ratio of an internal transcript, Ty1i, 4 3 to the genomic Ty1 transcript. Ty1i RNA encodes a dominant negative inhibitor of Ty1 retromobility 4 4 that blocks virus-like particle maturation and cDNA synthesis. These results resolve the conundrum of 4 5

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Truncated ORF1 proteins can suppress LINE-1 retrotransposition in trans

Cited by 23 publications

References 81 publications

The Mediator co-activator complex regulates Ty1 retromobility by controlling the balance between Ty1i and Ty1 promoters

The Mediator co-activator complex regulates Ty1 retromobility by controlling the balance between Ty1i and Ty1 promoters

Novel Bioinformatics Approach Identifies Transcriptional Profiles of Lineage-Specific Transposable Elements at Distinct Loci in the Human Dorsolateral Prefrontal Cortex

The Mediator co-activator complex regulates Ty1 retromobility by controlling the balance between Ty1i and Ty1 promoters

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