Albert Weixlbaumer
Biography - Albert Weixlbaumer
Institute of Genetics and Molecular and Cellular Biology (IGBMC), University of Strasbourg, CNRS and Inserm, France
Albert Weixlbaumer studied molecular biology at the University of Vienna, Austria. In 2004, he moved to the UK to join the group of Venki Ramakrishnan (Nobel Prize in Chemistry 2009) at the MRC Laboratory of Molecular Biology in Cambridge for his doctoral studies on the mechanism of protein synthesis. In 2008, he moved to the laboratory of Seth A. Darst for his postdoctoral research on the mechanism of transcription at the Rockefeller University in New York, USA. Dr. Weixlbaumer subsequently joined the IGBMC in 2014 to set up his own lab. He obtained a research scientist position at CR1 level (now CRCN) at the French National Institute of Health and Medical Research (Inserm) in 2014, and was promoted to research director in 2021 (DR2 level).
Albert Weixlbaumer’s lab addresses the regulation of transcription of RNA from DNA by RNA polymerase (Guo et al., Mol. Cell 2018; Abdelkareem et al., Mol Cell 2019; Zhu et al., Nat Comms 2022) as well as the interplay of macromolecular machineries involved in different aspects of gene expression (Webster et al., Science 2020). The team uses a combination of biochemistry and structural biology. The main focus is to use single particle cryo-EM and understand mechanistic aspects of the enzymes, which carry out gene expression. The lab was supported by the ATIP-Avenir program, an ERC Starting Grant, and by the French National Research Agency (ANR). Dr. Weixlbaumer was awarded the Prix Guy Ourisson 2018 by the Cercle Gutenberg, and the French research Coups d’élan prize by the Fondation Bettencourt-Schueller in 2021.
Project - The coupling of transcription and mRNA splicing
01/06/2022 - 31/05/2024
Gene expression is the first step to convert genotype to phenotype and it has to be tightly regulated. In complex organisms such as humans, gene expression occurs in three steps: 1) RNA polymerase II transcribes DNA to pre-mRNA; 2) pre-mRNA is processed to generate mature mRNA; and 3) mRNA is translated to protein by the ribosome.
In humans, mRNAs are transcribed as a mosaic of coding (exons) and non-coding (introns) sequences. Splicing, arguably the most critical aspect of pre-mRNA processing, removes introns and ligates exons to produce mature mRNAs, which are translated to protein. Splicing adds extra regulatory layers to gene expression. For example, mRNA splicing enables enormous proteome diversification because alternative splicing allows exon shuffling to produce different protein variants.
In vivo, splicing is carried out co-transcriptionally by a dynamic ribonucleoprotein particle called the spliceosome. The spliceosome assembles on the nascent pre-mRNA anew and is coupled to RNA polymerase II. RNA polymerase II 1) stimulates spliceosome assembly; 2) enables efficient splicing; and 3) plays decisive roles in the result of alternative splicing reactions. However, the mechanistic basis for any of these phenomena is not understood.
To close this gap, we will combine biochemistry and single particle cryo-EM to study the mechanism of co-transcriptional splicing. Using our expertise on large, dynamic complexes involved in gene expression, we will use purified components and nuclear extracts, which support splicing to assemble supramolecular complexes of RNA polymerase II and the spliceosome on different pre-mRNA substrates. We will study key reaction intermediates to understand how splicing occurs in the context of transcription, how RNA polymerase II stimulates splicing and how it affects the outcome of alternative splicing events. Our results will not only answer fundamental questions in biology but also provide the framework to develop strategies against erroneous splicing, which causes severe human diseases including many forms of cancer and neurodevelopmental disorders.
Post-doc biography - Geoffrey Gourinchas
Institute of Genetics and Molecular and Cellular Biology (IGBMC), University of Strasbourg, CNRS and Inserm, France
Geoffrey Gourinchas obtained a degree in biotechnological engineering from the École nationale supérieure de biotechnologie de Strasbourg (France) and the European Confederation of Upper Rhine Universities (EUCOR) in 2014, followed by a master's degree in structural biology, bioinformatics and biotechnologies from the University of Strasbourg. He then joined the Austrian Centre of Industrial Biotechnology (ACIB GmbH) in Graz, Austria, and developed multicistronic gene expression vectors for the expression of enzymatic pathways for the bioproduction of pure chiral molecules. In 2015, he started a PhD at the Graz University of Technology, where he focused on molecular mechanisms governing light signal transduction in bacterial infrared photoreceptors. In 2017, he published in the journal Sciences Advances the first atomic structure of a whole bacteriophytochrome coupled to an enzymatic effector, and integrated the structure with the analysis of the activation dynamics of the photoreceptor by hydrogen-deuterium exchange measured by mass spectrometry. Then, in 2018, he published the atomic structure of this whole bacteriophytochrome in an activated state in the journal eLife.
Being interested in protein engineering and allosteric dynamics within proteins, he joined the Max-Planck Institute for Biological Intelligence in Munich (Germany) in 2019, with a postdoctoral fellowship from the Alexander-von-Humboldt foundation. He was involved in the development of a fluorescent biosensor engineering method for in vivo imaging of synaptic plasticity events by CRISPR/Cas-based directed evolution in mammalian cells.
In 2022, Geoffrey Gourinchas joined the University of Strasbourg to use cryogenic electron microscopy to investigate the atomic structure of molecular machines involved in the coordination between DNA transcription and messenger RNA splicing in humans.
Links
- Homepage of Albert Weixlbaumer’s team at IGBMC - Regulation of transcription
- Institute of Genetics and Molecular and Cellular Biology (IGBMC)
