LS² Annual Meeting 2024

Title of the talk: The cis regulatory code of translational control during embryogenesis

Research plans:

The early stages of embryogenesis entail one of the most profound changes in the life of an organism. I use the zebrafish as a model of vertebrate embryogenesis, which differentiates from a single fertilized cell to an embryo with dozens of different cell types in a single day. Many transcriptional and posttranscriptional mechanisms regulate mRNA abundance as cells acquire their fate, but it is less understood how translational control shapes early embryogenesis. 

For translation to start, the ribosome must first engage with an mRNA at its most 5′ end. Then, it scans the 5′ untranslated region (5′ UTR) of the mRNA, until it encounters a codon to start protein synthesis. As such, the 5′ UTR is a point of control for selective mRNA translation and rate limiting for protein production. But what is the 5′ UTR regulatory logic that is at play during early vertebrate embryogenesis? How do embryos coordinate how much of each protein to make and when?

My future research group will investigate how translational regulation orchestrates vertebrate embryogenesis by studying the molecular mechanisms acting at the step of translation initiation. During my postdoctoral work, I developed an approach to interrogate at transcriptome scale how the initiation of mRNA translation is temporally coordinated by the 5′ UTR during zebrafish embryogenesis. This work identified dozens of short sequence motifs that are significantly overrepresented in 5′ UTRs displaying distinct translational behaviors during development. The majority are novel, and the remaining match the binding motifs of known RNA-binding proteins (RBPs) in other species. My future research program will focus on how 5′ UTRs and associated RBPs mediate temporal translational control during embryogenesis. 

We will build on this work and ask:
1. What is the cis-regulatory grammar of endogenous zebrafish 5′ UTRs?
2. Which RBPs regulate translation initiation via 5′ UTR motif binding during embryogenesis?
3. What are the developmental roles and molecular mechanisms of action of the identified RBPs?
4. What is the contribution of alternative 5′ UTR isoforms to differentiation and cell fate acquisition?

Significance: The exploratory nature of the aims promises to push the boundaries of our current understanding of the mechanisms driving translational control during vertebrate embryogenesis. We will identify the players acting via the 5′ UTR, understand the mechanisms by which they shape the translatome and how these molecular events impact tissue differentiation. Translational control is a key driver of cellular state transitions, and RBP dysfunction is associated with defects in stem cell maintenance, neurodegeneration and cancer. As such, and due to the high conservation of RBP consensus motifs and mechanisms of translation control, I anticipate that our findings will generate far-reaching insights into how translation control shapes cell fate acquisition. 

Title of the talk: DamAge: a multi-omic pan-tissue aging clock that quantifies macromolecular damage

Research plans:

Most theories and models of aging propose damage accumulation as a central cause of aging. Then why not directly quantify this damage and link it with aging phenotypes? That is the premise of DamAge, a pan-tissue human aging clock built on openly available datasets that directly quantifies age-related damage, and therefore aging itself, in biomolecules representing ~80% of the cell’s dry mass: proteins, RNA and lipids. 

My future lab will first build DamAge based on damaging post-translational protein modifications (PTMs): irreversible PTMs without known biological functions that increase with age (e.g. carboxyethyl). We will then infuse age-related RNA-damage (e.g. spurious splicing, intron retention, etc.) and lipid-damage (e.g. (per)oxidation products) into the DamAge clock. Finally, we will use DamAge to identify damage QTLs, genomic regions associated with variations in age-related damage, and their associated genes. We will assess their causal effects on lifespan, healthspan and non-communicable disease through Mendelian randomization. 

Significance: DamAge has the unique potential to assess how anti-aging interventions directly target the aging process rather than age-associated features. A multi-omic (transcriptome, proteome, and lipidome) damage clock also has the unique potential to quantify organelle-specific damage. This could reveal if certain organelles age faster than others, and if the relative rate of aging of different organelles is differentially affected in different diseases. Overall, with DamAge, biological age may for the first time be quantified directly through the essence of aging in health, disease and interventions.

Title of the talk: When Big Cells Break Bad: Investigating size-dependent genome homeostasis defects

Research plans:

Cellular senescence refers to a permanent state of cell cycle withdrawal. It is a tumour suppressive mechanism that prevents the propagation of cells that have experienced stresses, many of which cause genome instability. Still, cells can escape senescence under poorly-understood circumstances and progress into malignancies. Thus, characterising factors involved in senescence induction and maintenance is essential for understanding the genetic vulnerabilities that underpin cancer initiation.

Despite diverse drivers, it has long been observed that senescent cells are typically larger than cycling cells. I have recently shown that a prolonged G1 arrest (a consequence of many chemotherapies) is sufficient to induce senescence, whereas limiting cell growth under these conditions rescues proliferative potential. This suggests that increased cell size plays a functional role in senescence maintenance, but how this is conferred and how this affects essential cellular processes remains unknown.

I recently discovered that excess cell size destabilises the genome through a failure to mitigate replication stress and DNA double-strand breaks. These defects likely contribute to enlarged cells’ propensity for permanent cell cycle exit, but how they arise is not yet clear. My ongoing work seeks to address this by a) identifying cell cycle arrest drivers in enlarged cells; b) characterising the cause of replication-acquired DNA damage in enlarged cells; and c) uncovering why enlarged cells fail to repair double-strand breaks. This work will reveal how size-related genome homeostasis defects impact long-term cell fate and how this contributes to senescence induction as a barrier against cancer development.

Title of the talk: Connecting Nanoscale Dynamics to Pathways to Disease

Research plans:

The study of biomolecular dynamics at the nanoscale is central to unraveling the intricacies of the mechanisms of life and their dysfunction in disease. My laboratory is dedicated to studying phenomena that occur at this nanoscale, which are known to trigger pathological conditions but remain largely unexplained. For example, while it is known that tau proteins implicated in Alzheimer's disease form aggregates that lead to irreversible cellular damage, the precise molecular dynamics and the strategy for reversing these processes are still largely unknown. Similarly, the recently FDA-approved cancer treatment that significantly prolongs patient survival (30–50%) by combining chemotherapy with electric fields is promising, but the underlying mechanisms lack clear scientific consensus. Using my expertise in single-molecule experiments, methodological innovation, and physical modeling, I am committed to dissecting these complex molecular interactions.

By combining STED and single-molecule FRET (smFRET) with external perturbation studies, we aim to visualize and control the dynamics within biomolecules and their interactions at an unprecedented level. This multidimensional approach promises to significantly advance our understanding of cellular mechanisms, particularly in the areas of neurodegeneration and cancer treatment, and to open new avenues for potential medical applications.

Research Objectives:

1. Visualization of molecular aging at the single molecule level happening on the surface of biomolecular condensates associated with the onset and development of neurodegenerative diseases.
2. Modulation of weak interactions between biomolecules using external fields, like those employed in electric field cancer treatments, and to employ single-molecule spectroscopy and mesoscale approaches to understand and control these interactions at various scales, ultimately enhancing our ability to manipulate biomolecular functions for improved medical outcomes.

We are very pleased to announce that the special session "PIs of Tomorrow - The Future of Swiss Research" will be held at the LS² Annual Meeting 2024.

This session offers an opportunity for postdocs and junior researchers interested in pursuing an academic career to present a talk similar in format to a professorship application interview. A jury panel of professors will evaluate the presentations and provide feedback in a one-on-one session afterward. Only applicants with ties to Switzerland will be considered. As in 2019 in 2020, in 2021, in 2022, and in 2023 the PIOT session will be again a plenary session.

The PIs of Tomorrow chairs: Dr. Kathrin Tomasek, Dr. Nesli Ece Sen, Dr. Maria Giovanna De Leo, Dr. Erin Wosnitzka

APPLY HERE.

Download the full call bellow:

• • Lucia Prieto-Godino: 2017 Jury & Public Award Winner
    Awarded FENS EJN Young Investigator Prize, L’Oreal-UNESCO for women in science Fellowship
    Now Group Leader at the Francis Crick Institute (London, UK)
  • Alexander Harms: 2018 Jury Award Winner
    Awarded SNSF Ambizione
    Now Assistant Professor of Molecular Phage Biology at ETH Zurich (CH)
  • Andreas Moor: 2018 Public Award Winner
    Awarded SNSF Eccellenza, ERC Starting Grants
    Now Assistant Professor of Systems Physiology at ETH Zurich (CH)
  • Michael Zimmermann: 2019 Public Award Winner
    Awarded SNF Advanced Postdoc Mobility Fellowship, SwissTB Award, EMBO Long-Term Fellowship, SNF Early Postdoc.Mobility Fellowship Now Now Group Leader at EMBL (DE)
  • Francesca Ronchi: 2019 Jury Award co-Winner
    Awarded SNSF-MHV Postdoctoral fellowship, ECCO Grant
    Now Associate Professor at Charité – Universitätsmedizin Berlin (DE)
  • Jean-Philippe Krieger: 2019 Jury Award co-Winner
    Awarded an SNF postdoctoral fellowship
    Now PI at the VAGALAB and University of Gothenburg (Sweden) 
  • Thomas O. Auer: 2020 Jury Award Winner
    Awarded an Ambizione Fellowship, Now Assistant Professor at the University of Fribourg (CH) 
  • Joachim Moser von Filseck: 2020 Public Award Winner
    Now Research Group Leader at the Heidelberg University Biochemistry Center (DE) 
  • Elisa Araldi: 2021 Jury Award Winner
    Now Assistant ProfessorAssistant Professor at the Università degli Studi di Parma (IT) 
  • Karina Silina: 2021 Public Award Winner
    Now Senior Researcher at the Institute for Experimental Immunology, University of Zurich 
  • Alicia Michael:  2022 Jury Award Winner
    Now Postdoctoral Researcher at Friedrich Miescher Institute for Biomedical Research 
  • Adam Gosztolai: 2022 Public Award Winner
    Now a Human Frontiers Postdoctoral Fellow in the group of Pierre Vandergheynst at EPFL (CH) and Research Affiliate at Massachusetts Institute of Technology (US) 
  • Dr. Rubén Delgado Manzanedo: 2023 Jury Award Winner
    Now Lecturer at the Department of Environmental Systems Science, ETH Zurich (CH) 
  • Dr. Bernadette Jana Stolz-Pretzer: 2023 Public Award Winner
    Now Scientist at EPFL (CH)