Antiviral defence regulates intestinal function and overall gut health

New function of a known defence mechanism discovered: RNA interference not only fights viruses, it also regulates the protein balance of intestinal cells / Publication in ‘Nature Cell Biology’

Quelle: IDW Informationsdienst Wissenschaft

Anti-virale Abwehr reguliert Darmfunktion und Gesundheit

Neue Funktion eines bekannten Abwehrmechanismus entdeckt: Die RNA Interferenz bekämpft nicht nur Viren, sie reguliert auch das Proteingleichgewicht der Darmzellen / Veröffentlichung in „Nature Cell Biology“

Quelle: IDW Informationsdienst Wissenschaft

Two-billion-year-old enzyme reconstructed – Detective work by molecular biologists and bioinformatics researchers

Basic researchers at Leipzig University have solved a puzzle in the evolution of bacterial enzymes. By reconstructing a candidate for a special RNA polymerase as it existed about two billion years ago, they were able to explain a hitherto puzzling property of the corresponding modern enzymes. Unlike their ancestors, they do not work continuously and are thus significantly more effective – these pauses in activity constitute evolutionary progress. The reconstruction of the protein from prehistoric times was made possible thanks to interdisciplinary cooperation between molecular biochemistry and bioinformatics.

Quelle: IDW Informationsdienst Wissenschaft

Longer life due to faulty RNA processing

If introns remain in certain RNAs, worms live longer

The control of RNA metabolism is crucial to the regulation of animal longevity, researchers from the Max Planck Institute for Biology of Ageing in Cologne have now discovered. They found that worms live longer when certain RNAs are processed differently during RNA maturation. This could be an additional way for organisms to control the ageing process.

Quelle: IDW Informationsdienst Wissenschaft

RNA-Markierungen in Mitochondrien fördern invasive Ausbreitung von Krebs

Mitochondrien, die Kraftwerke der Zelle, enthalten eigenes Erbgut und eigene RNA-Moleküle. Ein Team vom Deutschen Krebsforschungszentrum fanden nun heraus: Bestimmte Markierungen der mitochondrialen RNA begünstigen die invasive Ausbreitung von Krebszellen. Genetische Marker für eine starke mitochondriale RNA-Markierung sind bei Patienten mit Kopf-Hals-Tumoren mit metastasierender Erkrankung verbunden.
Blockierten die Forscher in Krebszellen das für die RNA-Markierungen verantwortliche Enzym, so reduzierte dies die Anzahl der Metastasen. Auch Antibiotika, die die Proteinsynthese in den Mitochondrien unterdrücken, konnten die invasive Ausbreitung von Krebszellen im Laborversuch verhindern.

Quelle: IDW Informationsdienst Wissenschaft

DNA-Austausch zwischen Zellen: Welche Rolle spielen Exosomen in der Entwicklung von Krebs?

Fast alle Zelltypen sondern Exosomen ab: kleine extrazelluläre Vesikel, die mit Proteinen, RNA und DNA beladen sind. Auf diese Weise können Zellen untereinander kommunizieren und stimmen viele Prozesse ab, wie beispielsweise Zellteilungen. In der Nähe von Tumoren werden solche Exosomen verstärkt abgesondert. „Die darin enthaltenen Biomoleküle verändern die Umgebung von Tumoren und können damit den Verlauf einer Krebserkrankung entscheidend beeinflussen“, so PD Dr. Basant Kumar Thakur von der Kinderklinik III des Universitätsklinikums Essen und Wissenschaftler der Medizinischen Fakultät der Universität Duisburg-Essen.

Quelle: IDW Informationsdienst Wissenschaft

New “decision aid” for CRISPR immune responses

HIRI scientists show that target RNA levels influence defense against invaders

Quelle: IDW Informationsdienst Wissenschaft

A possible new COVID-19 vaccine could be accessible for more of the world

A new protein subunit vaccine may offer an inexpensive, easy-to-store, and effective alternative to RNA vaccines for COVID-19.

Quelle: Sciencedaily

RNA molecules control repair of human DNA in cancer cells

A new study shows how certain RNA molecules control the repair of damaged DNA in cancer cells, a discovery that could eventually give rise to better cancer treatments.

Quelle: Sciencedaily

Cinderella of chemical biology

Living organisms produce an abundance of small molecular compounds, called metabolites. Although, it is clear that small molecules are central to all aspect of life, their exact functionalities are often unknown. To fill this knowledge gap, and because small molecules act by binding with proteins, Aleksandra Skirycz’s group at the Max Planck Institute of Molecular Plant Physiology developed a novel strategy to identify such protein-molecule complexes. An important group of small molecules identified by this novel strategy are 2′,3′-cAMP nucleotides, which are products of RNA degradation and appear to play an important role in the regulation of stress responses.

Quelle: IDW Informationsdienst Wissenschaft

Research advances knowledge of the battle between viruses and human cells

In the long-term battle between a herpesvirus and its human host, a virologist and her team of students have identified some human RNA able to resist the viral takeover — and the mechanism by which that occurs.

Quelle: Sciencedaily

How a fungus hijacks our immune system

During infection, the yeast Candida albicans stimulates the release of tiny RNA fragments, which then stimulate its own growth. An international research team led by the Leibniz Institute for Natural Product Research and Infection Biology – Hans Knöll Institute (Leibniz-HKI) in Jena has discovered this unusual exploitation of the human immune system. The findings can explain disease processes and provide new approaches for the therapy of fungal infections. The results were published in the journal mBio.

Quelle: IDW Informationsdienst Wissenschaft

RNA ‘heroes’ can disarm bad-actor proteins in leukemia

Scientists believe it may be possible to prevent DNA changes driven by two proteins highly active in leukemia and other cancers. They recently reported a new mechanistic target for drug development.

Quelle: Sciencedaily

Genome study finds unexpected variation in a fundamental RNA gene

A genome study to look for variants in a gene considered a fundamental building block for microscopic structures that synthesize proteins took a surprising twist.

Quelle: Sciencedaily

RNA therapy for heart failure and organ fibrosis

RNA has already been making an impact in the context of the vaccine program, but the potential of RNA-based compounds is far from being fully tapped, as RNA allows for entirely new therapeutic approaches. Prof. Thomas Thum, Co-Institute Director of the Fraunhofer Institute for Toxicology and Experimental Medicine ITEM, has developed a form of RNA therapy for treating heart failure, which has already been successfully tested in patients as part of a phase 1b clinical trial. Other RNA therapies are currently being developed to treat pulmonary fibrosis and other forms of organ fibrosis.

Quelle: IDW Informationsdienst Wissenschaft

An unexpected attraction of nucleic acids and fat

Dresden scientists find that lipids modulate RNA activity, a possible clue to origin of life and tool for synthetic biology.

Quelle: IDW Informationsdienst Wissenschaft

‚Supermeres‘ may carry clues to cancer, Alzheimer’s disease and COVID-19

Researchers have discovered a nanoparticle released from cells, called a ’supermere,‘ which contains enzymes, proteins and RNA associated with multiple cancers, cardiovascular disease, Alzheimer’s disease and even COVID-19.

Quelle: Sciencedaily

New strategy against treatment-resistant prostate cancer identified

A new study has identified an RNA molecule that suppresses prostate tumors. The scientists found that prostate cancers develop ways to shut down this RNA molecule to allow themselves to grow. According to the new research — conducted in mice implanted with human prostate tumor samples — restoring this so-called long noncoding RNA could be a new strategy to treat prostate cancer that has developed resistance to hormonal therapies.

Quelle: Sciencedaily

Engineers devise a way to selectively turn on RNA therapies in human cells

Researchers have designed a way to selectively turn on gene expression in target cells, including human cells. Their technology can detect specific mRNA sequences, which triggers production of a specific protein.

Quelle: Sciencedaily

Sind zuckerhaltige RNA-Moleküle als Signalstoffe für das Immunsystem unterwegs?

Zuckerkristalle im polarisierten Licht unter dem Mikroskop. Wie  der Zucker an RNAs dockt, ist  noch rätselhaft.

Die RNA hat viele wichtige Funktionen in unserem Körper und wird seit kurzem auch als Corona-Impfstoff genutzt. Doch das Lebensmolekül ist längst noch nicht lückenlos durchschaut. Sind zuckerhaltige RNA-Moleküle als Signalstoffe für das Immunsystem unterwegs?

Quelle: FAZ.NET

Researchers identify new drug target for blood cancer, potentially solid tumors

Researchers have shown for the first time how mutations affecting a cellular process called RNA splicing alter cells to develop myelodysplastic syndrome (MDS) and other hematologic malignancies and solid tumors.

Quelle: Sciencedaily

Super-enhancers: The villain fueling certain cancers

Researchers identified a small RNA molecule called miR-766-5p that reduces expression of MYC, a critical cancer-promoting gene. This microRNA reduces levels of proteins CBP and BRD4, which are both involved in super-enhancer (SE) formation. SEs form in areas of DNA that can fuel MYC expression and tumor progression. This study provides strong evidence for developing miR-766-5p as a novel therapeutic to treat MYC-driven cancers.

Quelle: Sciencedaily

A global assessment of cancer genomic alterations in epigenetic mechanisms

Muhammad A Shah, Emily L Denton, Cheryl H Arrowsmith, Mathieu Lupien and Matthieu Schapira

Abstract

Background

The notion that epigenetic mechanisms may be central to cancer initiation and progression is supported by recent next-generation sequencing efforts revealing that genes involved in chromatin-mediated signaling are recurrently mutated in cancer patients.

Results

Here, we analyze mutational and transcriptional profiles from TCGA and the ICGC across a collection 441 chromatin factors and histones. Chromatin factors essential for rapid replication are frequently overexpressed, and those that maintain genome stability frequently mutated. We identify novel mutation hotspots such as K36M in histone H3.1, and uncover a general trend in which transcriptional profiles and somatic mutations in tumor samples favor increased transcriptionally repressive histone methylation, and defective chromatin remodeling.

Conclusions

This unbiased approach confirms previously published data, uncovers novel cancer-associated aberrations targeting epigenetic mechanisms, and justifies continued monitoring of chromatin-related alterations as a class, as more cancer types and distinct cancer stages are represented in cancer genomics data repositories.

Continue reading „A global assessment of cancer genomic alterations in epigenetic mechanisms“

Three-dimensional super-resolution microscopy of the inactive X chromosome territory reveals a collapse of its active nuclear compartment harboring distinct Xist RNA foci

3D-SIM-based DAPI intensity classification in the Barr body versus the entire nucleus of C2C12 cells. (A) Mid z-section of a DAPI-stained nucleus. The area below the dashed line illustrates the resolution level obtained by wide-field deconvolution microscopy, for comparison. Inset magnifications show the non-uniformly compacted structure of the Barr body resolvable with 3D-SIM (1) and an arbitrary autosomal region with CDCs (2). Scale bars: 5 μm, insets 1 μm. (B) X chromosome-specific painting (green) of Xi (left) and Xa territories (right) of the same nucleus in different z-sections. Note the high convergence between the painted Xi and the DAPI visualized Barr body (arrowheads). Scale bars: 2 μm, insets 1 μm. (C) 3D DAPI intensity classification exemplified for the nucleus shown in (A). Seven DAPI intensity classes displayed in false-color code ranging from class 1 (blue) representing pixels close to background intensity, largely representing the IC, up to class 7 (white) representing pixels with highest density, mainly associated with chromocenters. Framed areas of the Barr body (inset 1) and a representative autosomal region (inset 2) are shown on the right at resolution levels of 3D-SIM, deconvolution and conventional wide-field microscopy. The Xi territory pervaded by lower DAPI intensities becomes evident only at 3D-SIM resolution, whereas both wide-field and deconvolution microscopy imply a concentric increase of density in the Barr body. In the autosomal region, chromatin assigned to classes 2 to 3 lines compacted CDCs, represented by classes 4 to 6. (D) Left: average DAPI intensity classification profiles with standard deviations evaluated for entire nuclear volumes or the Barr body region only (dark grey bars). Right: over/underrepresentation of the average DAPI intensity class fraction sizes in the Barr body versus entire nuclear volumes (n = 12). Distribution differences on classes between Xi and entire nucleus P <0.001. 3D-SIM, three-dimensional structured illumination microscopy; CDC, chromatin domain cluster; DAPI, 4',6-diamidino-2-phenylindole; FISH, fluorescence in situ hybridization; IC, interchromatin compartment; Xa, active X chromosome; Xi, inactive X chromosome. Smeets et al. Epigenetics & Chromatin 2014 7:8   doi:10.1186/1756-8935-7-8
3D-SIM-based DAPI intensity classification in the Barr body versus the entire nucleus of C2C12 cells. (A) Mid z-section of a DAPI-stained nucleus. The area below the dashed line illustrates the resolution level obtained by wide-field deconvolution microscopy, for comparison. Inset magnifications show the non-uniformly compacted structure of the Barr body resolvable with 3D-SIM (1) and an arbitrary autosomal region with CDCs (2). Scale bars: 5 μm, insets 1 μm. (B) X chromosome-specific painting (green) of Xi (left) and Xa territories (right) of the same nucleus in different z-sections. Note the high convergence between the painted Xi and the DAPI visualized Barr body (arrowheads). Scale bars: 2 μm, insets 1 μm. (C) 3D DAPI intensity classification exemplified for the nucleus shown in (A). Seven DAPI intensity classes displayed in false-color code ranging from class 1 (blue) representing pixels close to background intensity, largely representing the IC, up to class 7 (white) representing pixels with highest density, mainly associated with chromocenters. Framed areas of the Barr body (inset 1) and a representative autosomal region (inset 2) are shown on the right at resolution levels of 3D-SIM, deconvolution and conventional wide-field microscopy. The Xi territory pervaded by lower DAPI intensities becomes evident only at 3D-SIM resolution, whereas both wide-field and deconvolution microscopy imply a concentric increase of density in the Barr body. In the autosomal region, chromatin assigned to classes 2 to 3 lines compacted CDCs, represented by classes 4 to 6. (D) Left: average DAPI intensity classification profiles with standard deviations evaluated for entire nuclear volumes or the Barr body region only (dark grey bars). Right: over/underrepresentation of the average DAPI intensity class fraction sizes in the Barr body versus entire nuclear volumes (n = 12). Distribution differences on classes between Xi and entire nucleus P Smeets et al. Epigenetics & Chromatin 2014 7:8 doi:10.1186/1756-8935-7-8

Daniel Smeets, Yolanda Markaki, Volker J Schmid, Felix Kraus, Anna Tattermusch, Andrea Cerase, Michael Sterr, Susanne Fiedler, Justin Demmerle, Jens Popken, Heinrich Leonhardt, Neil Brockdorff, Thomas Cremer1, Lothar Schermelleh and Marion Cremer

Abstract

Background

A Xist RNA decorated Barr body is the structural hallmark of the compacted inactive X territory in female mammals. Using super-resolution three-dimensional structured illumination microscopy (3D-SIM) and quantitative image analysis, we compared its ultrastructure with active chromosome territories (CTs) in human and mouse somatic cells, and explored the spatio-temporal process of Barr body formation at onset of inactivation in early differentiating mouse embryonic stem cells (ESCs).

Results

We demonstrate that all CTs are composed of structurally linked chromatin domain clusters (CDCs). In active CTs the periphery of CDCs harbors low-density chromatin enriched with transcriptionally competent markers, called the perichromatin region (PR). The PR borders on a contiguous channel system, the interchromatin compartment (IC), which starts at nuclear pores and pervades CTs. We propose that the PR and macromolecular complexes in IC channels together form the transcriptionally permissive active nuclear compartment (ANC). The Barr body differs from active CTs by a partially collapsed ANC with CDCs coming significantly closer together, although a rudimentary IC channel system connected to nuclear pores is maintained. Distinct Xist RNA foci, closely adjacent to the nuclear matrix scaffold attachment factor-A (SAF-A) localize throughout Xi along the rudimentary ANC. In early differentiating ESCs initial Xist RNA spreading precedes Barr body formation, which occurs concurrent with the subsequent exclusion of RNA polymerase II (RNAP II). Induction of a transgenic autosomal Xist RNA in a male ESC triggers the formation of an ‘autosomal Barr body’ with less compacted chromatin and incomplete RNAP II exclusion.

Conclusions

3D-SIM provides experimental evidence for profound differences between the functional architecture of transcriptionally active CTs and the Barr body. Basic structural features of CT organization such as CDCs and IC channels are however still recognized, arguing against a uniform compaction of the Barr body at the nucleosome level. The localization of distinct Xist RNA foci at boundaries of the rudimentary ANC may be considered as snap-shots of a dynamic interaction with silenced genes. Enrichment of SAF-A within Xi territories and its close spatial association with Xist RNA suggests their cooperative function for structural organization of Xi.

Continue reading „Three-dimensional super-resolution microscopy of the inactive X chromosome territory reveals a collapse of its active nuclear compartment harboring distinct Xist RNA foci“