Mechanism and Regulation of P Element Transposition

P elements were first discovered in the fruit fly Drosophila melanogaster as the causative agents of a syndrome of aberrant genetic traits called hybrid dysgenesis. This occurs when P element-carrying -males mate with females that lack P elements and results in progeny displaying sterility, mutations and chromosomal rearrangements. Since then numerous genetic, developmental, biochemical and structural studies have culminated in a deep understanding of P element transposition: from the cellular regulation and repression of transposition to the mechanistic details of the transposase nucleoprotein complex. Recent studies have revealed how piwi-interacting small RNA pathways can act to control splicing of the P element pre-mRNA to modulate transposase production in the germline. A recent cryo-electron microscopy structure of the P element transpososome reveals an unusual DNA architecture at the transposon termini and shows that the bound GTP cofactor functions to position the transposon ends within the transposase active site. Genome sequencing efforts have shown that there are P element transposase-homologous genes (called THAP9) in other animal genomes, including humans). This review highlights recent and previous studies, which together have led to new insights, and surveys our current understanding of the biology, biochemistry, mechanism and regulation of P element transposition.Human Frontier Science Program (CDA-00032/2018

L(3)mbt and the LINT complex safeguard cellular identity in the Drosophila ovary.

Maintenance of cellular identity is essential for tissue development and homeostasis. At the molecular level, cell identity is determined by the coordinated activation and repression of defined sets of genes. The tumor suppressor L(3)mbt has been shown to secure cellular identity in Drosophila larval brains by repressing germline-specific genes. Here, we interrogate the temporal and spatial requirements for L(3)mbt in the Drosophila ovary, and show that it safeguards the integrity of both somatic and germline tissues. l(3)mbt mutant ovaries exhibit multiple developmental defects, which we find to be largely caused by the inappropriate expression of a single gene, nanos, a key regulator of germline fate, in the somatic ovarian cells. In the female germline, we find that L(3)mbt represses testis-specific and neuronal genes. At the molecular level, we show that L(3)mbt function in the ovary is mediated through its co-factor Lint-1 but independently of the dREAM complex. Together, our work uncovers a more complex role for L(3)mbt than previously understood and demonstrates that L(3)mbt secures tissue identity by preventing the simultaneous expression of original identity markers and tissue-specific misexpression signatures

Reducing the environmental impact of surgery on a global scale: systematic review and co-prioritization with healthcare workers in 132 countries

Abstract Background Healthcare cannot achieve net-zero carbon without addressing operating theatres. The aim of this study was to prioritize feasible interventions to reduce the environmental impact of operating theatres. Methods This study adopted a four-phase Delphi consensus co-prioritization methodology. In phase 1, a systematic review of published interventions and global consultation of perioperative healthcare professionals were used to longlist interventions. In phase 2, iterative thematic analysis consolidated comparable interventions into a shortlist. In phase 3, the shortlist was co-prioritized based on patient and clinician views on acceptability, feasibility, and safety. In phase 4, ranked lists of interventions were presented by their relevance to high-income countries and low–middle-income countries. Results In phase 1, 43 interventions were identified, which had low uptake in practice according to 3042 professionals globally. In phase 2, a shortlist of 15 intervention domains was generated. In phase 3, interventions were deemed acceptable for more than 90 per cent of patients except for reducing general anaesthesia (84 per cent) and re-sterilization of ‘single-use’ consumables (86 per cent). In phase 4, the top three shortlisted interventions for high-income countries were: introducing recycling; reducing use of anaesthetic gases; and appropriate clinical waste processing. In phase 4, the top three shortlisted interventions for low–middle-income countries were: introducing reusable surgical devices; reducing use of consumables; and reducing the use of general anaesthesia. Conclusion This is a step toward environmentally sustainable operating environments with actionable interventions applicable to both high– and low–middle–income countries

Epigenetic control of repeat elements and its impact on genome activity in the model plant arabidopsis

La méthylation de l ADN joue un rôle majeur dans le contrôle de l activité des génomes de plantes et de mammifères. Cette marque épigénétique cible principalement les séquences répétées et notamment les éléments transposables (TE), dont elle réprime l activité. Chez les plantes, la perte de méthylation induite génétiquement a été décrite comme transmise de manière stable au cours des générations. Ces observations ont conduit à l idée que la méthylation de l ADN ne peut être restaurée après qu elle a été compromise. Nous montrons par une analyse systématique menée chez la plante un modèle Aradidopsis thaliana que cette idée n est qu en partie vraie. Nos travaux mettent en évidence l existence d un mécanisme de correction des défauts de méthylation, basé sur l interférence ARN (RNAi). Ce processus de reméthylation vise spécifiquement les séquences répétées ciblées par l ARNi, et est associé à la ré-inactivation des TE. Néanmoins, l ARNi ne contribue que peu au niveau global de méthylation, qui est majoritairement maintenu par la machinerie de maintenance . Enfin, nous montrons que contrairement aux simples mutants, les mutants affectés simultanément dans les deux voies de méthylation présentent une dérégulation de l expression de nombreux gènes ainsi que des altérations phénotypiques sévères et à pénétrance complète. Cette dérégulation génique massive n est pas due à une interférence transcriptionnelle mais aux effets secondaires de la dérégulation d un petit nombre de gènes contrôlés par la méthylation de l ADN. L ensemble de nos résultats dévoilent un rôle indispensable de l ARNi dans la préservation de l intégrité fonctionnelle et structurelle des génomes de plantes.DNA methylation is an epigenetic and mark that plays key roles in the control of genome activity in mammals and plants. It is mostly found associated with transposable elements (TEs) and is essential for TE silencing, thus protecting the genome against the deleterious effects of TE activity. In plants however, genetically induced loss of DNA methylation was shown to be stably transmitted independently f the inducing signal, leading to the view that DNA methylation cannot be restored once it has been compromised. Here, we show through a systematic analysis of genetically induced hypomethylation in the model plant Arabidopsis thaliana that this view is incorrect. Our results show existence of an RNA interference (RNAi)-based mechanism that protects numerous sequences against irremediable loss of DNA methylation. Remethylation process is specific to the fraction of repeats targeted by the RNAi machinery, does not spread into flanking regions, and is associated with re-silencing of TEs. Nevertheless, RNAi machinery is mostly dispensable for overall DNA methylation, which instead requires maintenance mechanisms. Finally, we show that in contrast to single mutants, double mutants impaired simultaneously in maintenance and RNAi- dependent DNA methylation pathways are associated with misregulation of numerous genes and overt and fully penetrant phenotypic alterations. This widespread gene misregulation is not caused by massive transcriptional interference, but instead from secondary effects of a subset or genes controlled by DNA methylation. Altogether, these results indicate an essential role of RNAi in preserving the structural and functional integrity of plant genomes.ORSAY-PARIS 11-BU Sciences (914712101) / SudocSudocFranceF

The cellular basis of hybrid dysgenesis and Stellate regulation in Drosophila

During normal tissue development, the accumulation of unrepaired cellular and genomic damage can impair growth and ultimately leads to death. To preserve cellular integrity, cells employ a number of defense mechanisms including molecular checkpoints, during which development is halted while dedicated pathways attempt repair. This process is most critical in germline tissues where cellular damage directly threatens an organism's reproductive capacity and offspring viability. In the fruit fly, Drosophila melanogaster, germline development has been extensively studied for over a century and the breadth of our knowledge has flourished in the genomics age. Intriguingly, several peculiar phenomena that trigger catastrophic germline damage described decades ago, still endure only a partial understanding of the underlying molecular causes. A deeper reexamination using new molecular and genetic tools may greatly benefit our understanding of host system biology. Among these, and the focus of this concise review, are hybrid dysgenesis and an intragenomic conflict that pits the X and Y sex chromosomes against each other

Mechanism and Regulation of P Element Transposition

Peer reviewed: TrueP elements were first discovered in the fruit fly Drosophila melanogaster as the causative agents of a syndrome of aberrant genetic traits called hybrid dysgenesis. This occurs when P element-carrying -males mate with females that lack P elements and results in progeny displaying sterility, mutations and chromosomal rearrangements. Since then numerous genetic, developmental, biochemical and structural studies have culminated in a deep understanding of P element transposition: from the cellular regulation and repression of transposition to the mechanistic details of the transposase nucleoprotein complex. Recent studies have revealed how piwi-interacting small RNA pathways can act to control splicing of the P element pre-mRNA to modulate transposase production in the germline. A recent cryo-electron microscopy structure of the P element transpososome reveals an unusual DNA architecture at the transposon termini and shows that the bound GTP cofactor functions to position the transposon ends within the transposase active site. Genome sequencing efforts have shown that there are P element transposase-homologous genes (called THAP9) in other animal genomes, including humans). This review highlights recent and previous studies, which together have led to new insights, and surveys our current understanding of the biology, biochemistry, mechanism and regulation of P element transposition.Human Frontier Science Program (CDA-00032/2018

Mechanism and regulation of P element transposition.

P elements were first discovered in the fruit fly Drosophila melanogaster as the causative agents of a syndrome of aberrant genetic traits called hybrid dysgenesis. This occurs when P element-carrying males mate with females that lack P elements and results in progeny displaying sterility, mutations and chromosomal rearrangements. Since then numerous genetic, developmental, biochemical and structural studies have culminated in a deep understanding of P element transposition: from the cellular regulation and repression of transposition to the mechanistic details of the transposase nucleoprotein complex. Recent studies have revealed how piwi-interacting small RNA pathways can act to control splicing of the P element pre-mRNA to modulate transposase production in the germline. A recent cryo-electron microscopy structure of the P element transpososome reveals an unusual DNA architecture at the transposon termini and shows that the bound GTP cofactor functions to position the transposon ends within the transposase active site. Genome sequencing efforts have shown that there are P element transposase-homologous genes (called THAP9) in other animal genomes, including humans. This review highlights recent and previous studies, which together have led to new insights, and surveys our current understanding of the biology, biochemistry, mechanism and regulation of P element transposition