Institute of Molecular Biology IMB

Mainz, Germany

Institute of Molecular Biology IMB

Mainz, Germany
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Roignant J.-Y.,Institute of Molecular Biology IMB | Soller M.,University of Birmingham
Trends in Genetics | Year: 2017

Modifications in mRNA constitute ancient mechanisms to regulate gene expression post-transcriptionally. N6-methyladenosine (m6A) is the most prominent mRNA modification, and is installed by a large methyltransferase complex (the m6A ‘writer’), not only specifically bound by RNA-binding proteins (the m6A ‘readers’), but also removed by demethylases (the m6A ‘erasers’). m6A mRNA modifications have been linked to regulation at multiple steps in mRNA processing. In analogy to the regulation of gene expression by miRNAs, we propose that the main function of m6A is post-transcriptional fine-tuning of gene expression. In contrast to miRNA regulation, which mostly reduces gene expression, we argue that m6A provides a fast mean to post-transcriptionally maximize gene expression. Additionally, m6A appears to have a second function during developmental transitions by targeting m6A-marked transcripts for degradation. © 2017 Elsevier Ltd

Lence T.,Institute of Molecular Biology IMB | Akhtar J.,Institute of Molecular Biology IMB | Bayer M.,Institute of Molecular Biology IMB | Schmid K.,Johannes Gutenberg University Mainz | And 8 more authors.
Nature | Year: 2016

N6-methyladenosine RNA (m6A) is a prevalent messenger RNA modification in vertebrates. Although its functions in the regulation of post-transcriptional gene expression are beginning to be unveiled, the precise roles of m6A during development of complex organisms remain unclear. Here we carry out a comprehensive molecular and physiological characterization of the individual components of the methyltransferase complex, as well as of the YTH domain-containing nuclear reader protein in Drosophila melanogaster. We identify the member of the split ends protein family, Spenito, as a novel bona fide subunit of the methyltransferase complex. We further demonstrate important roles of this complex in neuronal functions and sex determination, and implicate the nuclear YT521-B protein as a main m6A effector in these processes. Altogether, our work substantially extends our knowledge of m6A biology, demonstrating the crucial functions of this modification in fundamental processes within the context of the whole animal.

Busch A.,University of California at Irvine | Busch A.,Institute of Molecular Biology IMB | Hertel K.J.,University of California at Irvine
RNA | Year: 2015

Alternative splicing is a key player in the creation of complex mammalian transcriptomes and its misregulation is associated with many human diseases. Multiple mRNA isoforms are generated from most human genes, a process mediated by the interplay of various RNA signature elements and trans-acting factors that guide spliceosomal assembly and intron removal. Here, we introduce a splicing predictor that evaluates hundreds of RNA features simultaneously to successfully differentiate between exons that are constitutively spliced, exons that undergo alternative 5′ or 3′ splice-site selection, and alternative cassette-type exons. Surprisingly, the splicing predictor did not feature strong discriminatory contributions from binding sites for known splicing regulators. Rather, the ability of an exon to be involved in one or multiple types of alternative splicing is dictated by its immediate sequence context, mainly driven by the identity of the exon's splice sites, the conservation around them, and its exon/intron architecture. Thus, the splicing behavior of human exons can be reliably predicted based on basic RNA sequence elements. © 2015 Busch and Hertel.

Jeschke M.,Institute of Molecular Biology IMB | Baumgartner S.,Institute of Molecular Biology IMB | Legewie S.,Institute of Molecular Biology IMB
PLoS Computational Biology | Year: 2013

Cells reliably sense environmental changes despite internal and external fluctuations, but the mechanisms underlying robustness remain unclear. We analyzed how fluctuations in signaling protein concentrations give rise to cell-to-cell variability in protein kinase signaling using analytical theory and numerical simulations. We characterized the dose-response behavior of signaling cascades by calculating the stimulus level at which a pathway responds ('pathway sensitivity') and the maximal activation level upon strong stimulation. Minimal kinase cascades with gradual dose-response behavior show strong variability, because the pathway sensitivity and the maximal activation level cannot be simultaneously invariant. Negative feedback regulation resolves this trade-off and coordinately reduces fluctuations in the pathway sensitivity and maximal activation. Feedbacks acting at different levels in the cascade control different aspects of the dose-response curve, thereby synergistically reducing the variability. We also investigated more complex, ultrasensitive signaling cascades capable of switch-like decision making, and found that these can be inherently robust to protein concentration fluctuations. We describe how the cell-to-cell variability of ultrasensitive signaling systems can be actively regulated, e.g., by altering the expression of phosphatase(s) or by feedback/feedforward loops. Our calculations reveal that slow transcriptional negative feedback loops allow for variability suppression while maintaining switch-like decision making. Taken together, we describe design principles of signaling cascades that promote robustness. Our results may explain why certain signaling cascades like the yeast pheromone pathway show switch-like decision making with little cell-to-cell variability. © 2013 Jeschke et al.

Niehrs C.,German Cancer Research Center | Niehrs C.,Institute of Molecular Biology IMB | Acebron S.P.,German Cancer Research Center
Cell | Year: 2010

Two key events in Wnt signal transduction, receptor endocytosis and inactivation of Glycogen Synthase Kinase 3 (GSK3), remain incompletely understood. Taelman et al. (2010) discover that Wnt signaling inactivates GSK3 by sequestering the enzyme in multivesicular bodies, thus linking these two events and providing a new framework for understanding Wnt signaling. © 2010 Elsevier Inc.

Thakurela S.,Institute of Molecular Biology IMB | Sahu S.K.,Institute of Molecular Biology IMB | Garding A.,Institute of Molecular Biology IMB | Tiwari V.K.,Institute of Molecular Biology IMB
Genome Research | Year: 2015

Gene regulation in mammals involves a complex interplay between promoters and distal regulatory elements that function in concert to drive precise spatiotemporal gene expression programs. However, the dynamics of the distal gene regulatory landscape and its function in the transcriptional reprogramming that underlies neurogenesis and neuronal activity remain largely unknown. Here, we performed a combinatorial analysis of genome-wide data sets for chromatin accessibility (FAIREseq) and the enhancer mark H3K27ac, revealing the highly dynamic nature of distal gene regulation during neurogenesis, which gets progressively restricted to distinct genomic regions as neurons acquire a post-mitotic, terminally differentiated state. We further find that the distal accessible and active regions serve as target sites for distinct transcription factors that function in a stage-specific manner to contribute to the transcriptional program underlying neuronal commitment and maturation. Mature neurons respond to a sustained activity of NMDA receptors by epigenetic reprogramming at a large number of distal regulatory regions as well as dramatic reorganization of super-enhancers. Such massive remodeling of the distal regulatory landscape in turn results in a transcriptome that confers a transient loss of neuronal identity and gain of cellular plasticity. Furthermore, NMDA receptor activity also induces many novel prosurvival genes that function in neuroprotective pathways. Taken together, these findings reveal the dynamics of the distal regulatory landscape during neurogenesis and uncover novel regulatory elements that function in concert with epigenetic mechanisms and transcription factors to generate the transcriptome underlying neuronal development and activity. © 2015 Thakurela et al.

Ohkawara B.,German Cancer Research Center | Glinka A.,German Cancer Research Center | Niehrs C.,German Cancer Research Center | Niehrs C.,Institute of Molecular Biology IMB
Developmental Cell | Year: 2011

The R-Spondin (Rspo) family of secreted Wnt modulators is involved in development and disease and holds therapeutic promise as stem cell growth factors. Despite growing biological importance, their mechanism of action is poorly understood. Here, we show that Rspo3 binds syndecan 4 (Sdc4) and that together they activate Wnt/PCP signaling. In Xenopus embryos, Sdc4 and Rspo3 are essential for two Wnt/PCP-driven processes-gastrulation movements and head cartilage morphogenesis. Rspo3/PCP signaling during gastrulation requires Wnt5a and is transduced via Fz7, Dvl, and JNK. Rspo3 functions by inducing Sdc4-dependent, clathrin-mediated endocytosis. We show that this internalization is essential for PCP signal transduction, suggesting that endocytosis of Wnt-receptor complexes is a key mechanism by which R-spondins promote Wnt signaling. © 2011 Elsevier Inc.

de Albuquerque B.F.M.,Institute of Molecular Biology IMB | de Albuquerque B.F.M.,University of Porto | Placentino M.,Institute of Molecular Biology IMB | Ketting R.F.,Institute of Molecular Biology IMB
Developmental Cell | Year: 2015

The Piwi-piRNA pathway represents a germline-specific transposon-defense system. C. elegans Piwi, prg-1, is a non-essential gene and triggers a secondary RNAi response that depends on mutator genes, endo-siRNAs (22G-RNAs), and the 22G-RNA-binding Argonaute protein HRDE-1. Interestingly, silencing of PRG-1 targets can become PRG-1 independent. This state, known as RNAe, is heritable and depends on mutator genes and HRDE-1. We studied how the transgenerational memory of RNAe and the piRNA pathway interact. We find that maternally provided PRG-1 is required for de novo establishment of 22G-RNA populations, especially those targeting transposons. Strikingly, attempts to re-establish 22G-RNAs in absence of both PRG-1 and RNAe memory result in severe germline proliferation defects. This is accompanied by a disturbed balance between gene-activating and -repressing 22G-RNA pathways. We propose a model in which CSR-1 prevents the loading of HRDE-1 and in which both PRG-1 and HRDE-1 help to keep mutator activity focused on the proper targets. © 2015 Elsevier Inc.

Rippe K.,German Cancer Research Center | Luke B.,Institute of Molecular Biology IMB
Nature Structural and Molecular Biology | Year: 2015

Long noncoding telomeric repeat-containing RNA (TERRA) has been implicated in telomere maintenance in a telomerase-dependent and a telomerase-independent manner during replicative senescence and cancer. TERRA's proposed activities are diverse, thus making it difficult to pinpoint the critical roles that TERRA may have. We propose that TERRA orchestrates different activities at chromosome ends in a manner that depends on the state of the telomere. © 2015 Nature America, Inc. All rights reserved.

Cremer T.,LMU Biozentrum | Cremer C.,Institute of Molecular Biology IMB | Lichter P.,German Cancer Research Center
Human Genetics | Year: 2014

In line with the intentions of an issue celebrating the 50th anniversary of Human Genetics, we focus on a series of frequently cited studies published in this journal during the 1980s and 1990s. These studies have contributed to the rise of molecular cytogenetics. They yielded evidence that chromosomes occupy distinct territories in the mammalian cell nucleus, first obtained with laser-UV-microbeam experiments and thereafter with chromosome painting, and contributed to the development of interphase cytogenetics and comparative genome hybridization. We provide a personal account of experimental concepts, which were developed by us and others, and describe some of the unforeseeable turns and obstacles, which we had to overcome on the way towards an experimental realization. We conclude with a perspective on current developments and goals of molecular cytogenetics. © 2014 Springer-Verlag.

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