Chromatin remodeling and dna topology in transcription and genome stability

Eukaryotic DNA is wrapped around histone proteins to form nucleosomes, the fundamental repeati ng unit of chromatin. DNA packaging into chromatin both solves and creates problems. It allows the centimeters, or even meters, of DNA that constitute a eukaryotic genome to fit inside a micrometer - scale cell nucleus. Nucleosomes also block access to the D NA, necessitating complex rearrangements to allow for transcription, replication, recombination, or repair, while also providing a way to regulate these processes. ATP - dependent chromatin remodelers slide, assemble, disassemble, and alter nucleosomes to en able and regulate DNA - dependent processes. In parallel, topoisomerases relieve the tangles, torsional stress, and supercoils generated when DNA is exposed and unwound. Topoisomerases also enable efficient nucleosome remodeling. In this thesis, we use genom ewide and single - locus techniques to study the interplay between DNA topoisomerases, Snf2 family chromati n remodelers, and transcription in the fission yeast Schizosaccharomyces pombe. We find that topoisomerase activity is essential for transcription elon gation and for proper chromatin structure at genes, which in turn are required for efficient transcription initiation and termination. This is partially mediated by cooperation with chromatin remodelers. We also find that the fission yeast Chd1 subfamily r emodelers maintain correct gene body nucleosome positioning, which inhibits cryptic transcription initiation. Finally, we show that the Fun30 subfamily chromatin remodeler Fft2 is involved in centromere function and heterochromatic silencing, as well as th e full transcription of highly transcribed genes. Fft2 and its paralog Fft3 also regulate the transcriptional response to stress. As a part of this function, Fft2 and Fft3 repress retrotransposons by a novel mechanism, in which they enforce the use of an a lternative transcription start site

Reply to "CRISPR screens are feasible in TP53 wild-type cells"

Haapaniemi et al address the issues raised by Brown et al and discuss several differences between the analyses performed by the two groups.Non peer reviewe

Regulating retrotransposon activity through the use of alternative transcription start sites

International audienceRetrotransposons, the ancestors of retroviruses, have the potential for gene disruption and genomic takeover if not kept in check. Paradoxically, although host cells repress these elements by multiple mechanisms, they are transcribed and are even activated under stress conditions. Here, we describe a new mechanism of retrotransposon regulation through transcription start site (TSS) selection by altered nucleosome occupancy. We show that Fun30 chromatin remodelers cooperate to maintain a high level of nucleosome occupancy at retrotransposon-flanking long terminal repeat (LTR) elements. This enforces the use of a downstream TSS and the production of a truncated RNA incapable of reverse transcription and retrotransposition. However, in stressed cells, nucleosome occupancy at LTR elements is reduced, and the TSS shifts to allow for productive transcription. We propose that controlled retrotransposon transcription from a nonproductive TSS allows for rapid stress-induced activation, while preventing uncontrolled transposon activity in the genome

CRISPR-Cas9 genome editing induces a p53-mediated DNA damage response

Here, we report that genome editing by CRISPR-Cas9 induces a p53-mediated DNA damage response and cell cycle arrest in immortalized human retinal pigment epithelial cells, leading to a selection against cells with a functional p53 pathway. Inhibition of p53 prevents the damage response and increases the rate of homologous recombination from a donor template. These results suggest that p53 inhibition may improve the efficiency of genome editing of untransformed cells and that p53 function should be monitored when developing cell-based therapies utilizing CRISPR-Cas9.Peer reviewe

Mother–infant interaction in schizophrenia:Transmitting risk or resilience? A systematic review of the literature

Purpose: The parent–infant relationship is an important context for identifying very early risk and resilience factors and targets for the development of preventative interventions. The aim of this study was to systematically review studies investigating the early caregiver–infant relationship and attachment in offspring of parents with schizophrenia. Methods: We searched computerized databases for relevant articles investigating the relationship between early caregiver–infant relationship and outcomes for offspring of a caregiver with a diagnosis of schizophrenia. Studies were assessed for risk of bias. Results: We identified 27 studies derived from 10 cohorts, comprising 208 women diagnosed with schizophrenia, 71 with other psychoses, 203 women with depression, 59 women with mania/bipolar disorder, 40 with personality disorder, 8 with unspecified mental disorders and 119 non-psychiatric controls. There was some evidence to support disturbances in maternal behaviour amongst those with a diagnosis of schizophrenia and there was more limited evidence of disturbances in infant behaviour and mutuality of interaction. Conclusions: Further research should investigate both sources of resilience and risk in the development of offspring of parents with a diagnosis of schizophrenia and psychosis. Given the lack of specificity observed in this review, these studies should also include maternal affective disorders including depressive and bipolar disorders

Antagonism between DNA and H3K27 Methylation at the Imprinted Rasgrf1 Locus

At the imprinted Rasgrf1 locus in mouse, a cis-acting sequence controls DNA methylation at a differentially methylated domain (DMD). While characterizing epigenetic marks over the DMD, we observed that DNA and H3K27 trimethylation are mutually exclusive, with DNA and H3K27 methylation limited to the paternal and maternal sequences, respectively. The mutual exclusion arises because one mark prevents placement of the other. We demonstrated this in five ways: using 5-azacytidine treatments and mutations at the endogenous locus that disrupt DNA methylation; using a transgenic model in which the maternal DMD inappropriately acquired DNA methylation; and by analyzing materials from cells and embryos lacking SUZ12 and YY1. SUZ12 is part of the PRC2 complex, which is needed for placing H3K27me3, and YY1 recruits PRC2 to sites of action. Results from each experimental system consistently demonstrated antagonism between H3K27me3 and DNA methylation. When DNA methylation was lost, H3K27me3 encroached into sites where it had not been before; inappropriate acquisition of DNA methylation excluded normal placement of H3K27me3, and loss of factors needed for H3K27 methylation enabled DNA methylation to appear where it had been excluded. These data reveal the previously unknown antagonism between H3K27 and DNA methylation and identify a means by which epigenetic states may change during disease and development

Evaluating expert-based habitat suitability information of terrestrial mammals with GPS-tracking data

Aim Macroecological studies that require habitat suitability data for many species often derive this information from expert opinion. However, expert-based information is inherently subjective and thus prone to errors. The increasing availability of GPS tracking data offers opportunities to evaluate and supplement expert-based information with detailed empirical evidence. Here, we compared expert-based habitat suitability information from the International Union for Conservation of Nature (IUCN) with habitat suitability information derived from GPS-tracking data of 1,498 individuals from 49 mammal species. Location Worldwide. Time period 1998-2021. Major taxa studied Forty-nine terrestrial mammal species. Methods Using GPS data, we estimated two measures of habitat suitability for each individual animal: proportional habitat use (proportion of GPS locations within a habitat type), and selection ratio (habitat use relative to its availability). For each individual we then evaluated whether the GPS-based habitat suitability measures were in agreement with the IUCN data. To that end, we calculated the probability that the ranking of empirical habitat suitability measures was in agreement with IUCN's classification into suitable, marginal and unsuitable habitat types. Results IUCN habitat suitability data were in accordance with the GPS data (> 95% probability of agreement) for 33 out of 49 species based on proportional habitat use estimates and for 25 out of 49 species based on selection ratios. In addition, 37 and 34 species had a > 50% probability of agreement based on proportional habitat use and selection ratios, respectively. Main conclusions We show how GPS-tracking data can be used to evaluate IUCN habitat suitability data. Our findings indicate that for the majority of species included in this study, it is appropriate to use IUCN habitat suitability data in macroecological studies. Furthermore, we show that GPS-tracking data can be used to identify and prioritize species and habitat types for re-evaluation of IUCN habitat suitability data

Exploring anti-androgen therapies in hormone dependent prostate cancer and new therapeutic routes for castration resistant prostate cancer

Androgen deprivation therapies (ADTs) are important treatments which inhibit androgen-induced prostate cancer (PCa) progression by either preventing androgen biosynthesis (e.g. abiraterone) or by antagonizing androgen receptor (AR) function (e.g. bicalutamide, enzalutamide, darolutamide). A major limitation of current ADTs is they often remain effective for limited durations after which patients commonly progress to a lethal and incurable form of PCa, called castration-resistant prostate cancer (CRPC) where the AR continues to orchestrate pro-oncogenic signalling. Indeed, the increasing numbers of ADT-related treatment-emergent neuroendocrine-like prostate cancers (NePC), which lack AR and are thus insensitive to ADT, represents a major therapeutic challenge. There is therefore an urgent need to better understand the mechanisms of AR action in hormone dependent disease and the progression to CRPC, to enable the development of new approaches to prevent, reverse or delay ADT-resistance. Interestingly the AR regulates distinct transcriptional networks in hormone dependent and CRPC, and this appears to be related to the aberrant function of key AR-epigenetic coregulator enzymes including the lysine demethylase 1 (LSD1/KDM1A). In this review we summarize the current best status of anti-androgen clinical trials, the potential for novel combination therapies and we explore recent advances in the development of novel epigenetic targeted therapies that may be relevant to prevent or reverse disease progression in patients with advanced CRPC

''Det här skulle jag inte vilja skriva, men jag måste det'' : En kvalitativ studie om biståndshandläggares möjliga problematik vid handläggning av äldres sociala behov

Syfte: Att studera den problematik som biståndshandläggare kan tänkas uppleva när de handlägger äldres sociala behov. Metod: Studien använde ett kvalitativt tillvägagångssätt för att få en djupare förståelse för biståndshandläggare upplevelser av ensamma och isolerade äldre. Studien inkluderar fem semistrukturerade intervjuer med biståndshandläggare från 5 olika kommuner i Sverige. Insamlat material analyserades genom tematisk analys.Resultat: Den insamlade data som utvanns ur analysen sektionerades ut i sju teman, Handläggningen av äldres sociala behov, Vad är skäligt att bevilja? Vikten av sociala aktiviteter, vikten av den enskildes delaktighet, Handläggarens möjliga dilemman, Att hitta den bästa lösningen och Motivationen av ängsliga och ensamma äldre. Innehållet i resultatet riktar fokus på biståndshandläggares upplevelser av de svårigheter som existerar i handläggningsarbetet. Slutsats: Resultaten visar att handläggaren behöver tillgodose fler individers behov och önskningar än enbart den enskildes och sammanväva dessa för ett optimalt insatsbeslut som även gör politiker och organisationen nöjda. Resultaten visar också att handläggarna upplever att det kan vara svårt att göra en bedömning av äldres sociala behov. En av anledningen till detta är att handläggarna gemensamt lyfter att politikerna inte alltid lyssnar när handläggarna framför ett behov av att skapa nya insatser utifrån de äldres behov.Purpose: To study the problems that may appear when care managers manage the social needs of elderly people. Method: This study uses a qualitative approach to get a deeper understanding of care managers experiences with lonely and isolated elderly people. The study includes five semi structured interviews with care managers from 5 different municipalities of Sweden. The material collected was analyzed using thematic analysis.Results: The collected data that came from analyzing was sectioned out into seven themes, The managing of the elderly people’s social needs, what is a reasonable level of care to approve? The meaning of social activities, the meaning of including the individual, thepossible dilemmas of a care manager and motivating anxious and lonely elderlypeople. The content focuses on the experiences of care managers and the difficulties in their practice. Conclusion: The conclusion of this study ends up in a joint agreement of the difficulties of care managers. Problems including the politicians tightening of the economy. They mean that it creates unnecessary issues for the elderly