6 research outputs found
RNase H2, mutated in Aicardi-Goutières syndrome, promotes LINE-1 retrotransposition
Long INterspersed Element class 1 (LINE-1) elements are a type of
abundant retrotransposons active in mammalian genomes. An
average human genome contains ~100 retrotransposition-competent
LINE-1s, whose activity is influenced by the combined action
of cellular repressors and activators. TREX1, SAMHD1 and ADAR1
are known LINE-1 repressors and when mutated cause the autoinflammatory
disorder Aicardi-Goutières syndrome (AGS). Mutations
in RNase H2 are the most common cause of AGS, and its activity
was proposed to similarly control LINE-1 retrotransposition. It has
therefore been suggested that increased LINE-1 activity may be
the cause of aberrant innate immune activation in AGS. Here, we
establish that, contrary to expectations, RNase H2 is required for
efficient LINE-1 retrotransposition. As RNase H1 overexpression
partially rescues the defect in RNase H2 null cells, we propose a
model in which RNase H2 degrades the LINE-1 RNA after reverse
transcription, allowing retrotransposition to be completed. This
also explains how LINE-1 elements can retrotranspose efficiently
without their own RNase H activity. Our findings appear to be at
odds with LINE-1-derived nucleic acids driving autoinflammation
in AGS.M.B.-G. is funded by a âFormacion Profesorado
Universitarioâ (FPU) PhD fellowship from the Government of Spain (MINECO,
Ref FPU15/03294), and this paper is part of her thesis project (âEpigenetic
control of the mobility of a human retrotransposonâ). R.V.-A. is funded by a
PFIS Fellowship from the Government of Spain (ISCiii, FI16/00413). O.M. is
funded by an EMBO Long-Term Fellowship (ALTF 7-2015), the European
Commission FP7 (Marie Curie Actions, LTFCOFUND2013, GA-2013-609409) and
the Swiss National Science Foundation (P2ZHP3_158709). S.R.H. is funded by
the Government of Spain (MINECO, RYC-2016-21395 and SAF2015-71589-P).
A.P.Jâs laboratory is supported by the UK Medical Research Council (MRC University Unit grant U127527202). J.L.G.Pâs laboratory is supported by CICEFEDER-
P12-CTS-2256, Plan Nacional de I+D+I 2008-2011 and 2013-2016 (FISFEDER-
PI14/02152), PCIN-2014-115-ERA-NET NEURON II, the European
Research Council (ERC-Consolidator ERC-STG-2012-233764), by an International
Early Career Scientist grant from the Howard Hughes Medical Institute
(IECS-55007420), by The Wellcome Trust-University of Edinburgh Institutional
Strategic Support Fund (ISFF2) and by a private donation from Ms Francisca
Serrano (Trading y Bolsa para Torpes, Granada, Spain)
LINE-1 Evasion of Epigenetic Repression in Humans
Epigenetic silencing defends against LINE-1 (L1) retrotransposition in mammalian cells. However, the mechanisms that repress young L1 families and how L1 escapes to cause somatic genome mosaicism in the brain remain unclear. Here we report that a conserved Yin Yang 1 (YY1) transcription factor binding site mediates L1 promoter DNA methylation in pluripotent and differentiated cells. By analyzing 24 hippocampal neurons with three distinct single-cell genomic approaches, we characterized and validated a somatic L1 insertion bearing a 3' transduction. The source (donor) L1 for this insertion was slightly 5' truncated, lacked the YY1 binding site, and was highly mobile when tested in\ua0vitro. Locus-specific bisulfite sequencing revealed that the donor L1 and other young L1s with mutated YY1 binding sites were hypomethylated in embryonic stem cells, during neurodifferentiation, and in liver and brain tissue. These results explain how L1 can evade repression and retrotranspose in the human body
Clonal chromosomal mosaicism and loss of chromosome Y in elderly men increase vulnerability for SARS-CoV-2
The pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2, COVID-19) had an estimated overall case fatality ratio of 1.38% (pre-vaccination), being 53% higher in males and increasing exponentially with age. Among 9578 individuals diagnosed with COVID-19 in the SCOURGE study, we found 133 cases (1.42%) with detectable clonal mosaicism for chromosome alterations (mCA) and 226 males (5.08%) with acquired loss of chromosome Y (LOY). Individuals with clonal mosaic events (mCA and/or LOY) showed a 54% increase in the risk of COVID-19 lethality. LOY is associated with transcriptomic biomarkers of immune dysfunction, pro-coagulation activity and cardiovascular risk. Interferon-induced genes involved in the initial immune response to SARS-CoV-2 are also down-regulated in LOY. Thus, mCA and LOY underlie at least part of the sex-biased severity and mortality of COVID-19 in aging patients. Given its potential therapeutic and prognostic relevance, evaluation of clonal mosaicism should be implemented as biomarker of COVID-19 severity in elderly people. Among 9578 individuals diagnosed with COVID-19 in the SCOURGE study, individuals with clonal mosaic events (clonal mosaicism for chromosome alterations and/or loss of chromosome Y) showed an increased risk of COVID-19 lethality
The Biodiversity of the Mediterranean Sea: Estimates, Patterns, and Threats
The Mediterranean Sea is a marine biodiversity hot spot. Here we combined an extensive literature analysis with expert opinions to update publicly available estimates of major taxa in this marine ecosystem and to revise and update several species lists. We also assessed overall spatial and temporal patterns of species diversity and identified major changes and threats. Our results listed approximately 17,000 marine species occurring in the Mediterranean Sea. However, our estimates of marine diversity are still incomplete as yetâundescribed species will be added in the future. Diversity for microbes is substantially underestimated, and the deep-sea areas and portions of the southern and eastern region are still poorly known. In addition, the invasion of alien species is a crucial factor that will continue to change the biodiversity of the Mediterranean, mainly in its eastern basin that can spread rapidly northwards and westwards due to the warming of the Mediterranean Sea. Spatial patterns showed a general decrease in biodiversity from northwestern to southeastern regions following a gradient of production, with some exceptions and caution due to gaps in our knowledge of the biota along the southern and eastern rims. Biodiversity was also generally higher in coastal areas and continental shelves, and decreases with depth. Temporal trends indicated that overexploitation and habitat loss have been the main human drivers of historical changes in biodiversity. At present, habitat loss and degradation, followed by fishing impacts, pollution, climate change, eutrophication, and the establishment of alien species are the most important threats and affect the greatest number of taxonomic groups. All these impacts are expected to grow in importance in the future, especially climate change and habitat degradation. The spatial identification of hot spots highlighted the ecological importance of most of the western Mediterranean shelves (and in particular, the Strait of Gibraltar and the adjacent Alboran Sea), western African coast, the Adriatic, and the Aegean Sea, which show high concentrations of endangered, threatened, or vulnerable species. The Levantine Basin, severely impacted by the invasion of species, is endangered as well
An epi [c] genetic battle: LINE-1 retrotransposons and intragenomic conflict in humans
The ongoing activity of the human retrotransposon Long Interspersed Element 1 (LINE-1 or L1) continues to impact the human genome in various ways. Throughout evolution, mammalian and primate genomes have been under selection to generate strategies to reduce the activity of selfish DNA like L1. Similarly, selfish DNA has evolved to elude these containment systems. This intragenomic conflict has left many inactive versions of LINEs and other Transposable Elements (TEs) littering the human genome, which together account for roughly half of our DNA. Here, we survey the distinct mechanisms operating in the human genome that seem to reduce the mobility of L1s. In addition, we discuss recent findings that strongly suggest epigenetic mechanisms specifically regulate L1 activity in pluripotent human cells
Author Correction: Reprogramming triggers endogenous L1 and Alu retrotransposition in human induced pluripotent stem cells
This Article contains an error in the author affiliations. The correct affiliation for author Ruchi Shukla is âMRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Crewe Road, Edinburgh, EH4 2XU, UKâ, and is not âMater Research Institute â University of Queensland, TRI Building, Woolloongabba QLD 4102, Australiaâ