Notice: Dr Markus Höpfler is currently at the MRC Laboratory of Molecular Biology, in Cambridge, UK, and will join the CRG in spring 2025

Biosketch

2025 - Junior Group Leader, at the Centre for Genomic Regulation, Barcelona (Spain)
2021-2023 - Marie Skłodowska-Curie Postdoctoral Fellow, MRC Laboratory of Molecular Biology, Cambridge (UK)
2020-2021 - EMBO Postdoctoral Fellow, MRC Laboratory of Molecular Biology, Cambridge (UK)
2019-2024 - Postdoctoral Fellow, MRC Laboratory of Molecular Biology, Cambridge (UK); Advisor: Dr. Ramanujan Hegde
2019 - PhD in Biology, Ludwig-Maximilians-University Munich, and Max-Planck-Institute of Biochemistry, Martinsried (Germany); Advisors: Stefan Jentsch and Boris Pfander
2012-2013 - Research Associate, Medical University of Vienna (Austria); Advisor: Andrea Barta
2011 - Diploma in Molecular Biology,University of Vienna (Austria)
 

Research Summary

How do cells accurately tune protein production according to cellular needs? This fundamental question is not only fascinating but also crucial to human health: Aberrant protein levels are commonly linked to diseases such as developmental defects, cancer, or neurodegenerative diseases, where aggregation-prone proteins tend to accumulate in neurons.

In the “Dynamics of protein synthesis & RNA decay” lab we are interested in how cells tune protein production by adjusting the stability of messenger RNAs (mRNAs). Each cell in our body expresses around 12,000 different mRNAs at any given time. To control this complex transcriptome—and thus protein synthesis—cells adjust half-lives for individual mRNAs from minutes to several days. Traditionally, the selective degradation of mRNAs has been attributed to the recognition of nucleotide sequence elements by proteins or small RNAs that subsequently recruit decay factors. In our lab, we investigate a distinct, newly emerging paradigm of gene regulation termed “peptide-mediated mRNA decay” (PMD). In PMD, not the mRNA sequence but rather the nascent protein is recognized to trigger degradation of the encoding mRNA during its translation by the ribosome.

This process is exemplified by tubulin mRNAs, which are selectively degraded when cells sense excess free tubulins, the building blocks of the microtubule cytoskeleton. In this case, a recognition factor binds the nascent tubulin protein on the ribosome (see figure). Subsequently, an adapter protein and decay factors that execute mRNA degradation are recruited, as we and others recently demonstrated. Perturbed tubulin mRNA turnover results in severe phenotypes, such as cell division defects, impaired neurodevelopment, ciliopathies, and infertility. Beyond tubulins, emerging evidence points to critical PMD mechanisms targeting transcripts encoding aggregation-prone proteins when crucial chaperones are absent. Thus, PMD represents an unexplored paradigm of gene regulation that dynamically adjusts protein production to ensure cellular fitness. However, a mechanistic understanding of peptide-mediated mRNA decay is only beginning to emerge, and the scope of PMD substrates is completely unknown.
 

Using a highly interdisciplinary approach spanning biochemistry, structural biology, cell biology, genetics, and advanced sequencing methods, we aim to answer the following questions: What are the factors and molecular mechanisms driving peptide-mediated mRNA decay? How are these mechanisms controlled, and what are the consequences of impaired mRNA turnover for cells and organisms? What is the transcriptome-wide scope of regulation by peptide-mediated mRNA decay?

Answering these questions will be highly relevant to human biology and disease, as highlighted by the examples of tubulin and aggregation-prone proteins. Furthermore, insights into mRNA decay mechanisms will enable development of optimized mRNA-based therapeutics like mRNA vaccines.
 

Job Opportunities

We are always interested to hear from potential postdoctoral researchers, PhD students and technicians/research assistants that are interested in joining our lab. We are currently building an interdisciplinary team centred around biochemistry and cell biology, with some projects involving structural biology, next-generation sequencing or genetics approaches. Training in one or more of these disciplines and/or experience with RNA biology or microtubule biology will be beneficial. If you are excited about our research and are interested in joining the team, please reach out to Markus by email with a motivation letter and CV.