Mark your calendar! On January 17th, 2024, Hannes Klump, Director of Transfusion Medicine and Cell Therapeutics at the Uniklinik RWTH Aachen, will talk about

‘The quest for novel HOX-gene combinations promoting hematopoietic stem cell development from (i)PSCs.

Induced pluripotent stem (iPS-) cells may become a promising source for the generation of patient-specific hematopoietic stem cells (HSCs), in vitro. However, protocols allowing for the directed, efficient generation of HSCs with long-term multilineage repopulating properties do not exist yet. So far, the most robust strategy for generating hematopoietic progenitors from pluripotent cells, in vitro, has been established in the mouse model involving ectopic expression of the human transcription factor HOXB4, as we have repeatedly shown. Its enforced expression promotes the formation of hemogenic endothelium cells and their subsequent morphologic transition to early hematopoietic progenitors. Nevertheless, it is not sufficient to mediate a complete, final maturation to an adult phenotype comparable to bone-marrow resident HSCs, in vitro. Because of the paramount role of HOX-genes for development and maintenance of HSCs, one the aims of our lab is to identify combinations which allow for the de novo generation of fully mature HSPCs from differentiating mouse and human PSCs and, also, the expansion of adult HSPCs.

Join us for insights into exciting science on January 17th, 3 p.m., at the University Hospital Regensburg KUNO (Buildiung C5), room 3.552!

UPDATE – the seminar has been postponed to June 2nd 2020 (mark your calendar – you don’t want to miss out on the exciting data and findings that Sebastian is going to present!)

TALK CANCELED – Unfortunately Sebastian cannot make it on October 17th. We are trying to postpone the talk – stay tuned for updates…

‘Wenn du Tore schießen möchtest, musst du an der richtigen Stelle stehen’ (if you want to score goals you have to be in the right spot) – that’s what children get taught by their football trainers. If you want to be ‘the fox in the box’ positioning is very important.

This is also true for RNAs. Many mRNAs exhibit a specific sub-cellular localization allowing localized production of proteins. This is of importance in many biological settings: e.g. it equips synapses with a unique proteome, allows directed cell migration, and determines the body axes during early embryonic development.

In mammalian neurons, the asymmetric distribution of mRNAs and local protein synthesis is required for essential processes as cell polarization, migration and synaptic plasticity underlying long-term memory formation. However, the essential components driving cytoplasmic mRNA transport in neurons and mammalian cells are not known.

Mark your calendars: On October 17^th at 2p.m. in H53, Sebastian Maurer from the Centre for Genomic regulation (CRG) in Barcelona, Spain, will report the first reconstitution of a mammalian mRNA transport system. His studies reveal that the tumour suppressor adenomatous polyposis coli (APC) forms stable complexes with the axonally localised b-actin and b2B-tubulin mRNAs which are linked to a heterotrimeric kinesin-2 via the cargo adaptor KAP3. APC activates kinesin-2 and both proteins are sufficient to drive specific transport of defined mRNA packages. Guanine-rich sequences located in 3’UTRs of axonal mRNAs increase transport efficiency and balance the access of different mRNAs to the transport system. These findings establish for the first time a minimal set of proteins capable of driving kinesin-based, mammalian mRNA transport.

Some like it cold: (Body)temperature-controlled kinase activity in circadian biology, sex determination and beyond

In numerous animals (including crocodiles, alligators, tortoises, and some teleost fish), sex is determined independently of the genotype. Rather the temperature experienced during embryonic or larval stages results in the development of phenotypically male or female animals. Exemplarily, exposing alligator eggs to elevated temperatures produces mostly male offspring. The mechanism by which subtle changes in temperature are sensed to govern sex-specific development, however, has remained elusive.

On January 30th 2020 (2p.m. in H53), Florian Heyd from the Freie Universität Berlin will talk about protein kinases that act as very sensitive thermo-sensors to control changes to alternative splicing. The exciting work combines enzymology, structural-, and RNA biology to reveal in molecular detail how the activity of CDC-like kinases (CLKs) is altered by changes in temperature, resulting in differential phosphorylation of SR-proteins and subsequently in altered splicing patterns.

 

Click here for the advertisement of the talk.

 

Mark your calendars! On May 10th at 10a.m. in room VKL 5.1.31, Benedikt Beckmann will talk about novel methods to study RNA-protein interactions during bacterial infection (click here for the advert). Benedikt is a group leader at the Integrated Research Institute (IRI) for the Life Sciences in Berlin, an institute shared between the Humboldt University Berlin, the Charité University Clinic and the Max-Delbrück-Center for Molecular Medicine.

His research focuses on RNA-protein interactions in host cells during infection by pathogenic bacteria which he studies by employing classical molecular biology methods in combination with systems biology approaches and bioinformatics. Using Salmonella typhimurium as a model system, he investigates whether bacterial-derived non-coding RNAs and RNA-binding proteins can directly manipulate host cell gene expression on a post-transcriptional level e.g. to manipulate the immune repsponse of the host.

Recently, Bene established a novel methodological approach to generate RNA interactomes by employing organic extraction for the purification of UV cross-linked ribonucleoproteins (PTex). Previous methods relied on oligo-dT oligonucleotides to capture cross-linked RNPs by hybridization to the poly(A)-tail, limiting their applicability to eukaryotic organisms. Furthermore, Bene will talk about a recently developed machine learning-based tool for the de novo prediction of RNA-binding proteins across a wide variety of species (TriPepSVM).

 

Genomic intron densities are highly variable across species, ranging from many introns per transcript in humans to fewer than one per transcript in some microbes. The extremophilic red alga, Cyanidioschyzon merolae, has taken intron reduction to an extreme, harboring only ~40 introns in its 5000-gene genome. This raises the question of whether this alga contains the canonical set of splicing machinery, which in humans comprises 5 small, nuclear RNAs and over 200 proteins.

On September 21^st, Prof. Stephen D. Rader from the University of Northern British Columbia, Canada, will talk about ‘The Highly Reduced Spliceosome of C. merolae’. To study the biological role of this tiny intron complement, Stephen and his group have characterized the splicing machinery in C. merolae. Surprisingly, it is completely lacking the U1 snRNP, comprises only ~40 core proteins, has but a single LSm complex, and appears to have an RNA degradation complex associated with it.

The unexpected observation of apparent splicing regulatory proteins raised the possibility that the splicing events in C. merolae, few though they are, are regulated in response to environmental conditions or other cues. Stephen will discuss current efforts to investigate this possibility. The small size of the C. merolae spliceosome make this a promising system in which to study core features of the splicing pathway, as well as the evolutionary pressures that result in reduced splicing systems.

 

The sequence of the RNA is determined by the DNA template that encodes it. However, after synthesis it can be enzymatically altered. on August 31st, Dr. Konstantin Licht from the Center for Anatomy and Cell Biology of the Medicla University of Vienna from will talk about Adenosine deaminases acting on RNA (ADAR1 or ADAR2) enzymes that catalyze the conversion of Adenosine to Inosine (A-to-I editing). As Inosine is interpreted as guanosine by cellular machines A-to-I editing changes the sequence information of the RNA. This can affect the coding potential of the RNA and impacts on e.g. innate immunity and miRNA maturation. Moreover, de-regulation of editing has been linked to several pathologies including epilepsy, depression, and cancer.

Editing sites in protein-coding parts of transcripts are frequently defined by exon-intron base-pairing, and hence RNA splicing was predicted to control the extent of editing. Konstantin will present data that demonstrate that reduced splicing efficiency leads to increased editing levels when the exonic editing site is coordinated by an intron. Thus, the efficiency of splicing is of great importance for the level of editing.

Moreover, it was recently found that lethality associated with the ADAR1 knockout in mice can be rescued when proteins involved in the innate immune response (MDA5, MAVS) are also deleted. This allowed the generation of viable, editing-deficient mice (ADAR1/ADAR2 double-null mice) that were used to create the first high-confidence map of editing sites which suggest extensive cross-talk between splicing and editing.

August 10th, 2pm in H53: An exciting lecture you should definitely not miss! Ivo Telley from the Instituto Gulbenkian de Ciência in Oeiras, Portugal, will talk about the physical principles underlying nuclear division.

In Drosophila embryos, zygotic nuclei initially undergo rapid successive divisions without cytokinesis and, therefore, a vast number of nuclei share the same intracellular space in a syncytium. They need to be evenly distributed throughout a large cytoplasmic volume and brought to the cell cortex to form even-sized cells. The regular arrangement of the nuclei is vital to later embryo development, and defects that perturb this distribution are lethal. How the regular nuclear distribution during early divisions is achieved and maintained is an interesting yet unresolved question.

One of Ivo’s main research tracks is to understand the physical principles underlying the regular arrangement and precise positioning of nuclei, and the mechanism that maintain the regularity of the nuclear distribution during perturbations such as nuclear division. He will present new insight into the mechanics of nuclear distribution and point at microtubule-based molecular interactions that are involved in distance maintenance between nuclei. It is known that the microtubule cytoskeleton plays a key role in nuclear transport, and its dynamics is greatly determined by the microtubule-organizing center, the centrosome. Ivo has evidence from mitotic mutants which suggests that the centrosomes, and not the nuclei, are the spatial organizer in the early embryo.

Finally, he will present efforts in developing an extract approach to study young fertilized eggs and visualize pronuclei and sperm in time-lapse and high-resolution, something which has not been possible before. With this approach, he aims to study how Wolbachia infection in Drosophila affects the last stages of fertilization and, in particular, what causes the first mitotic division to fail.

 

 

At the Instituto Gulbenkian de Ciência in Oeiras, Portugal, Ivo is head of a multidisciplinary research team interested in the physical aspects of intracellular organization. As a model system, they study the earliest stage of Drosophila development, from the mature egg to fertilization to pre-blastoderm cleavages. They focus on pronuclear fusion in the fertilized egg and how the syncytial embryo defines the inter-nuclear distance between rapid mitotic divisions. They employ reconstitution approaches in egg explants combined with time-lapse light microscopy and image processing while taking advantage of Drosophila genetics. By applying this assay in a study of host-micro-organism interactions, they have started to investigate how Wolbachia infection in Drosophila affects the last stages of fertilization preceding developmental arrest due to cytoplasmic incompatibility.

 

 

One equals two!

While this simple statement gets most people shaking their heads in disbelief, we geneticists get all excited. It is about dosage compensation – intricate genetic programs that ensure an equal gene dose from different numbers of chromosomes.

Why is that important? Most higher eukaryotes reproduce sexually, allowing them to combine alleles from two different individuals thus increasing variability in the offspring and resulting in the cleansing of harmful mutations from a population. Sexual reproduction usually requires animals of two different sexes: males and females. Although numerous exceptions exist, the two sexes typically differ in the number of X chromosomes. However, it is critical for survival that the genetic output from different numbers of X chromosomes is matched. This poses a big challenge to gene expression. In nature several different strategies have been invented to achieve a comparable gene dose in the two different sexes by either reducing the genetic output from two X chromosomes or by boosting transcription of the single X chromosome.

Drosophila melanogaster has long served as a genetic model system to study dosage compensation in molecular detail. Female flies carry two X chromosomes (XX) and males one (XY). Dosage compensation is achieved by hypertranscription of the single, male X chromosome, essentially doubling its output. But how is this achieved on a molecular level?

On May 23^rd, Peter Becker from the Ludwig-Maximilians-University in Munich will talk about how flies assemble a remarkable regulator to boost transcription of the single male X chromosome. Join us at 5p.m. in H53 for exciting science!

 

In December we will have another great talk: Elmar Wahle from the Martin-Luther Universität Halle-Wittenberg will present exciting findings regarding ‘Post-transcriptional regulation of maternal mRNA during early embryonic development: The nanos mRNA of Drosophila‘.

During the early development of animal embryos, the zygotic nucleus is not transcribed. Instead, protein synthesis is driven by maternal mRNAs that were synthesized during oocyte development and stockpiled in an inactive state. Thus, regulation of protein synthesis in early embryos is post-transcriptional. A prominent example is the nanos mRNA of Drosophila, regulation of which is essential for the formation of the anterior-posterior axis of the embryo (see also here). Synthesis of the Nanos protein is driven by small fraction of nanos mRNA that is localized at the posterior pole. The bulk of nanos mRNA is distributed uniformly throughout the embryo and is translationally repressed and decays gradually.

Elmar and his team are investigating the mechanisms controlling translational repression and degradation of the non-localized nanos mRNA. Some of the proteins that they have identified as constituents of the repressor complex are universally involved in translational repression and mRNA degradation, suggesting that their findings may have significance beyond the regulation of maternal mRNAs.

So mark your calendar and join us for exciting science on December 8th at 2p.m. in H53!

 

 

On tuesday next week, Jean Yves Roignant from the institute of Molecular Biology (IMB) in Mainz will present intriguing findings that highlight the importance of m⁶A RNA modification in flies.

N⁶-methyladenosine RNA (m⁶A) is a prevalent mRNA modification in vertebrates. While its functions in the regulation of posttranscriptional gene expression are beginning to be unveiled, the precise roles of m⁶A during development of complex organisms remain unclear. Jean-Yves and his team have carried out a comprehensive molecular and physiological characterization of the individual components of the methyltransferase complex as well as of the YTH nuclear reader protein in Drosophila melanogaster. They identified the member of the split ends protein family, Spenito, as a novel bona fide subunit of the methyltransferase complex. Furthermore, they demonstrated important roles of this complex in neuronal function and sex determination, and implicate the nuclear YT521-B as a main m⁶A effector in these processes. Altogether, this work substantially extends our knowledge on m⁶A biology, demonstrating the crucial functions of this modification in fundamental processes within the context of the whole animal.

Join us on November 22nd at 5p.m. in H53 for some exciting science!

 

Save the date! On August second 5p.m. in H53, Mandy Jeske from the EMBL in Heidelberg will give a talk entitled: Exploring molecular mechanisms in the germ plasm.

Germ cells are an integral part of sexual reproduction. To segregate the germline from soma, during early development many animals assemble a specialized cytoplasm, which is called germ plasm. The molecular mechanisms that take place in and define the germ plasm are poorly understood.

In her talk Mandy Jeske from the EMBL in Heidelberg will discuss molecular functions of the Drosophila germ plasm nucleation protein Oskar. She will present the recently solved crystal structures of Oskar and discuss activities of previously uncharacterized protein domains. Furthermore, she will address the molecular functions of Vasa, a germ-line specific DEAD-box RNA helicase involved in the secondary piRNA pathway, and how a novel class of protein domains regulates Vasa’s enzymatic activity.

We are very much looking forward to Mandy’s visit, a fascinating talk and exciting discussions!

Mark your calendar! On July 21st, Andrea Pauli from the Research Institute of Molecular Pathology (IMP), Vienna, Austria, will visit the University of Regensburg. Her major research interest is the function of short open reading frames in zebrafish development.

Recent findings have indicated that eukaryotic translation is far more complex than anticipated with the frequent translation of short open reading frames that were previously overlooked. This ‘pervasive translation’ includes regions that are predicted to encode short, conserved proteins, while other translated regions lack signatures of protein conservation and might serve gene-regulatory functions. This raises two important questions: what is the role of the translated regions in the regulation of gene expression, and what are the functions of the newly discovered short proteins/petides? In her talk entitled ‘Found in translation: from genomics to novel gene functions in zebrafish’ (2p.m. in H53), Andrea will share exciting insights into the functions and regulatory principles of these newly discovered short translated open reading frames (ORFs) employing zebrafish embryogenesis as a model system.

.