Ancient exapted transposable elements promote nuclear enrichment of human long noncoding RNAs

Carlevaro-Fita, Joana; Polidori, Taisia; Das, Monalisa; Navarro, Carmen; Zoller, Tatjana I.; Johnson, Rory

doi:10.1101/gr.229922.117

Cited by 66 publications

(44 citation statements)

References 83 publications

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“…Importantly, an RNA sequence derived from SINE/Alu elements was recently shown to be sufficient to drive nuclear retention of some long non-coding RNAs (Chen, 2018;Lubelsky and Ulitsky, 2018), thus suggesting a pathway for nuclear accumulation of both lncRNAs and mRNAs that contain such sequences. Furthermore, removal of repeat sequences from some nuclear lincRNAs has been shown to cause them to relocalize to the cytosol (Carlevaro-Fita et al, 2017). Our APEX-seq data are consistent with these previous studies and further suggest that SINE/Alu-associated nuclear localization is due to preferential localization of these transposable-derived RNAs to the nuclear lamina.…”

Section: Rna Repeats and Genomic Position Correlate With Nuclear Rna supporting

confidence: 91%

Atlas of Subcellular RNA Localization Revealed by APEX-seq

Fazal

Han

Kaewsapsak

et al. 2018

Preprint

112

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We introduce APEX-seq, a method for RNA sequencing based on spatial proximity to the peroxidase enzyme APEX2. APEX-seq in nine distinct subcellular locales produced a nanometer-resolution spatial map of the human transcriptome, revealing extensive and exquisite patterns of localization for diverse RNA classes and transcript isoforms. We uncover a radial organization of the nuclear transcriptome, which is gated at the inner surface of the nuclear pore for cytoplasmic export of processed transcripts. We identify two distinct pathways of messenger RNA localization to mitochondria, each associated with specific sets of transcripts for building complementary macromolecular machines within the organelle. APEX-seq should be widely applicable to many systems, enabling comprehensive investigations of the spatial transcriptome.(ERM), which we previously attempted but failed to map using APEX2-ERM and APEX-RIP (Kaewsapsak et al., 2017). When we performed a comparison of APEX-seq and APEX-RIP using HEK 239T cells expressing APEX on the ER membrane (facing the cytosol), we found that APEX-seq could clearly enrich secretory mRNAs on the ER membrane over cytosolic mRNAs, whereas APEX-RIP could not ( Figure 1D). Given the very close proximity between ER membrane-associated RNAs and cytosolic RNAs that are immediately adjacent to the ER, these results suggest that APEX-seq has a labeling radius of only a few nanometers. Validation of APEX-seqEncouraged by the results above, we expanded APEX-seq to nine distinct subcellular locations ( Figure 1E). Correct localization of each APEX2 fusion protein (domain structures shown in Figure S2A) in HEK-293T cells was confirmed by imaging with organelle markers ( Figure 1F). We prepared two replicates for each location ( Figure S2B and S2C, correlation coefficient r between replicates ranged from 0.97 to 1) as well as negative controls in which H2O2 was omitted from the labeling reaction. After labeling for 1 minute and cell lysis, we enriched biotinylated RNAs and prepared APEX-seq libraries with polyA+ selection. Transcripts shorter than 100 nt were excluded during purification. We used DESeq2 (Love et al., 2014) for data analysis and used a qvalue (FDR-adjusted p-value) < 0.05 and a log2fold-change > 0.75 to select for significantly enriched transcripts.Consistent with the RT-qPCR results for the mitochondrial matrix shown in Figure 1C, our sequencing-based analysis showed that all 13 mRNAs and 2 rRNAs encoded by mtDNA are strongly enriched by MITO-APEX2 labeling (Figure 2A, S2D and S2E, mean enrichment > 11fold), whereas no mRNAs encoded by the nuclear genome are enriched. Figure 2B shows good correlation (r > 0.9) between technical replicates.To assess APEX-seq in an "open" subcellular region (not enclosed by a membrane), we focused again on the ER membrane (ERM). The ERM is particularly valuable for methodology validation because there are well-established "true positives" (mRNAs encoding secreted proteins that are known to be translated at the ERM) and well-established "false positive...

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Section: Rna Repeats and Genomic Position Correlate With Nuclear Rna supporting

confidence: 91%

Atlas of Subcellular RNA Localization Revealed by APEX-seq

Fazal

Han

Kaewsapsak

et al. 2018

Preprint

112

View full text Add to dashboard Cite

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“…How the nuclear export of long RNAs is regulated remains poorly understood. Specific sequences regulating nuclear retention have been identified in individual lncRNAs (Miyagawa et al 2012;Zhang et al 2014;Carlevaro-Fita et al 2019), and more recently using massively parallel screens (Lubelsky and Ulitsky 2018;Shukla et al 2018;Yin et al 2018), but most RNAs retained in the nucleus do not contain any sequence elements associated with a known effect on nuclear export.…”

Section: Introductionmentioning

confidence: 99%

Predictive models of subcellular localization of long RNAs

Zuckerman

Ulitsky

2019

RNA

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Export to the cytoplasm is a key regulatory junction for both protein-coding mRNAs and long noncoding RNAs (lncRNAs), and cytoplasmic enrichment varies dramatically both within and between those groups. We used a new computational approach and RNA-seq data from human and mouse cells to quantify the genome-wide association between cytoplasmic/ nuclear ratios of both gene groups and various factors, including expression levels, splicing efficiency, gene architecture, chromatin marks, and sequence elements. Splicing efficiency emerged as the main predictive factor, explaining up to a third of the variability in localization. Combination with other features allowed predictive models that could explain up to 45% of the variance for protein-coding genes and up to 34% for lncRNAs. Factors associated with localization were similar between lncRNAs and mRNAs with some important differences. Readily accessible features can thus be used to predict RNA localization.

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“…A major part of vertebrate l ncRNAs and lincRNAs contains TE-derived sequences (Fig. 1 c), the estimations ranging from 50 to over 80% depending on the study and the species considered [ 183 – 186 ]. Within lincRNAs, which experience the same maturation steps as pre-mRNAs of protein-coding genes but are frequently poorly spliced [ 187 ], TE-derived sequences are preferentially found in introns and then in exons and promoters in mammals [ 185 ].…”

Section: Tes As a Source Of New Non-coding Rna Genesmentioning

confidence: 99%

Transposable element-derived sequences in vertebrate development

et al. 2021

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Transposable elements (TEs) are major components of all vertebrate genomes that can cause deleterious insertions and genomic instability. However, depending on the specific genomic context of their insertion site, TE sequences can sometimes get positively selected, leading to what are called “exaptation” events. TE sequence exaptation constitutes an important source of novelties for gene, genome and organism evolution, giving rise to new regulatory sequences, protein-coding exons/genes and non-coding RNAs, which can play various roles beneficial to the host. In this review, we focus on the development of vertebrates, which present many derived traits such as bones, adaptive immunity and a complex brain. We illustrate how TE-derived sequences have given rise to developmental innovations in vertebrates and how they thereby contributed to the evolutionary success of this lineage.

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Ancient exapted transposable elements promote nuclear enrichment of human long noncoding RNAs

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Cited by 66 publications

References 83 publications

Atlas of Subcellular RNA Localization Revealed by APEX-seq

Atlas of Subcellular RNA Localization Revealed by APEX-seq

Predictive models of subcellular localization of long RNAs

Transposable element-derived sequences in vertebrate development

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