<i>Alu</i>retrotransposons promote differentiation of human carcinoma cells through the aryl hydrocarbon receptor

Morales-Hernández, Antonio; González-Rico, Francisco J.; Román, Ángel; Rico-Leo, Eva M.; Alvarez-Barrientos, Alberto; Sánchez, Laura; Macia, Ángela; Heras, Sara R.; García‐Pérez, José L.; Merino, Jaime M.; Fernández-Salguero, Pedro M.

doi:10.1093/nar/gkw095

Cited by 49 publications

(88 citation statements)

References 64 publications

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“…Hence, although Ahr expression in ES cells is under the control of the network of pluripotency factors, an increase of AHR expression is likely to counteract the maintenance of pluripotency and to induce exit from the pluripotent state. Consistent with this idea, recent studies reveal that AHR turns off the expression of OCT4 and NANOG through Alu -transposon transcription during differentiation of human embryonic teratocarcinoma cells [37], suggesting that AHR may activate a mechanism that controls the expression of pluripotency genes in both pluripotent and differentiation states.…”

Section: Potential Mechanisms Through Which Ahr Modulates Pluripotmentioning

confidence: 78%

Does the aryl hydrocarbon receptor regulate pluripotency?

Puga

2017

Current Opinion in Toxicology

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Recent evidence from embryonic stem cells suggests that the aryl hydrocarbon receptor (AHR) plays a central role in the regulation of pluripotency, a short-lived property of cells in the early blastula inner cell mass (ICM). Four key observations support this conclusion. The first is the temporal association between upregulation of AHR expression and the onset of cell differentiation, which argues for the AHR as a determinant of cell fate decisions. The second is the repression of the pluripotency factors OCT4 and NANOG by the AHR, which depresses their function and contributes to the cell's exit from pluripotency. The third is the temporal association between changes in global DNA methylation and stage-dependent AHR expression, which parallel each other during embryonic development, suggesting that AHR helps configure a repressive chromatin structure that controls differentiation. The fourth is the incidence of early developmental aberrations that take place in Ahr-null mice and cause the disruption of their embryonic program, which is likely to be a consequence of the loss of pluripotency of the Ahr−/− ICM cells. In this short review, we will focus on the modulation of pluripotency as a novel function of the AHR, and on the potentially detrimental developmental outcomes that may result from exposure to environmental toxicants. This line of enquiry brings us to the tantalizing conclusion that by activating mechanisms that modulate pluripotency, AHR regulates embryonic development. The likelihood that exposure to environmental AHR ligands might disrupt developmental processes is a reasonable corollary to this conclusion.

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Section: Potential Mechanisms Through Which Ahr Modulates Pluripotmentioning

confidence: 78%

Does the aryl hydrocarbon receptor regulate pluripotency?

Puga

2017

Current Opinion in Toxicology

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“…Alu expression contribution to genome regulation involves multiple mechanisms, and different approaches have been used to study it, including the analysis of RNA polymerase III activity, retrotransposition, noncoding RNAs, Alu mediated adenosine to inosine (A-to-I) RNA editing, and exonization among others (Oler et al 2012;Daniel et al 2015;Tajnik et al 2015;Varshney et al 2015;Klawitter et al 2016;Lin et al 2016;Moráles-Hernandez et al 2016;Nishikura 2016). Therefore, unveiling the specific contribution of each element to genome regulation requires targeted customized studies.…”

Section: Epigenetic and Functional Features Of Transcribed Alu Repeatsmentioning

confidence: 99%

The epigenetic landscape of Alu repeats delineates the structural and functional genomic architecture of colon cancer cells

et al. 2016

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Cancer cells exhibit multiple epigenetic changes with prominent local DNA hypermethylation and widespread hypomethylation affecting large chromosomal domains. Epigenome studies often disregard the study of repeat elements owing to technical complexity and their undefined role in genome regulation. We have developed NSUMA (Next-generation Sequencing of UnMethylated Alu), a cost-effective approach allowing the unambiguous interrogation of DNA methylation in more than 130,000 individual Alu elements, the most abundant retrotransposon in the human genome. DNA methylation profiles of Alu repeats have been analyzed in colon cancers and normal tissues using NSUMA and whole-genome bisulfite sequencing. Normal cells show a low proportion of unmethylated Alu (1%-4%) that may increase up to 10-fold in cancer cells. In normal cells, unmethylated Alu elements tend to locate in the vicinity of functionally rich regions and display epigenetic features consistent with a direct impact on genome regulation. In cancer cells, Alu repeats are more resistant to hypomethylation than other retroelements. Genome segmentation based on high/low rates of Alu hypomethylation allows the identification of genomic compartments with differential genetic, epigenetic, and transcriptomic features. Alu hypomethylated regions show low transcriptional activity, late DNA replication, and its extent is associated with higher chromosomal instability. Our analysis demonstrates that Alu retroelements contribute to define the epigenetic landscape of normal and cancer cells and provides a unique resource on the epigenetic dynamics of a principal, but largely unexplored, component of the primate genome.

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“…Some of these functional impacts are generated by RIs inserted in genes because of the A/T richness of the LINE-1 sequence (Han et al 2004) and due to the presence of a poly-A tail at the 3´end of the retrotransposon insertion (in both LINEs and SINEs), which can increase the repertoire of transcripts produced from the targeted gene (i.e., generating alternative transcripts). Similarly, Alu elements carry a functional polymarase-III promoter that can directly influence gene expression (Murphy and Baralle 1983); additionally, selected Alu insertions can affect the expression of targeted genes by additional mechanisms (Levanon et al 2004;Pandey and Mukerji 2011;Elbarbary et al 2013;Morales-Hernández et al 2016). Indeed, the AluYg6 insertion on chr1q25.3 identified in this study ( Figure 3C-D) seems to directly impact EDEM3 gene expression, as an alternative annotated transcriptional variant in humans terminates precisely in the AluYg6 poly-A tail.…”

Section: The Impact Of Ris In Modern Humansmentioning

confidence: 66%

Impact of non-LTR retrotransposons in the differentiation and evolution of Anatomically Modern Humans

Guichard

Peona

Malagoli-Tagliazucchi

et al. 2017

Preprint

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Transposable Elements are biologically important components of eukaryote genomes. In particular, non-LTR retrotransposons (N-LTRrs) extensively shaped the human genome throughout evolution. In this study, we compared retrotransposon insertions differentially present in the genomes of Anatomically Modern Humans, Neanderthals, Denisovans and Chimpanzees, in order to assess the possible impact of retrotransposition in the differentiation of the human lineage. Briefly, we first identified species-specific N-LTRrs and established their distribution in present day human populations. These analyses shortlisted a group of N-LTRr insertions that were found exclusively in Anatomically Modern Humans. Notably, these insertions targeted genes more frequently than randomly expected and are associated with an increase in the number of transcriptional/splicing variants of those genes they inserted in. The analysis of the functionality of genes targeted by human-specific N-LTRr insertions seems to reflect phenotypic changes that occurred during human evolution. Furthermore, the expression of genes containing the most recent N-LTRr insertions is enriched in the brain, especially in undifferentiated neurons, and these genes associate in networks related to neuron maturation and migration. Additionally, we also identified candidate N-LTRr insertions that have likely produced new functional variants exclusive to modern humans, which show traces of positive selection and are now fixed in all present-day human populations. In sum, our results strongly suggest that N-LTRr impacted our differentiation as a species and have been a constant source of genomic variability all throughout the evolution of the human lineage.

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Aluretrotransposons promote differentiation of human carcinoma cells through the aryl hydrocarbon receptor

Cited by 49 publications

References 64 publications

Does the aryl hydrocarbon receptor regulate pluripotency?

Does the aryl hydrocarbon receptor regulate pluripotency?

The epigenetic landscape of Alu repeats delineates the structural and functional genomic architecture of colon cancer cells

Impact of non-LTR retrotransposons in the differentiation and evolution of Anatomically Modern Humans

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