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UPF Biomedical Research Symposium 2021

  • Fechas:

    Del 14/10/21 al 14/10/21

  • Lugar:

    Online, Barcelona, España (mapa)

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Abstracts

Juan Martín-Serrano

Coordination Of Membrane Remodelling To Reform And Repair The Nuclear Envelope 

The reformation of the nuclear envelope (NE) after mitosis re-establishes the structural integrity and the functionality of the nuclear compartment. The endosomal sorting complex required for transport (ESCRT) machinery, a conserved membrane remodeling pathway, is involved in NE resealing by mediating the annular fusion of the nuclear membrane. I will discuss how CC2D1B, a regulator of ESCRT polymerization, is required to re-establish the nuclear compartmentalization by coordinating endoplasmic reticulum (ER) membrane deposition around chromatin disks with ESCRT-III recruitment to the reforming NE. Critically, CC2D1B licenses the formation of ESCRT-III polymers to ensure the orderly reformation of the NE, and this activity is essential to re-establish an intact nuclear compartment.

Besides the mitotic reformation of the NE, efficient repair of transient nuclear envelope ruptures during interphase (NERDI) ensures the compartmentalization of the nucleus. NERDIs can occur due to cytoskeletal compressive forces at sites of weakened lamina. NE resealing requires the local polymerization and membrane remodelling by the ESCRT machinery. I will reveal how NE compressive forces are counteracted to allow efficient membrane resealing after NERDI. Specifically, we identify the ESCRT-associated protein BROX as a crucial factor required to accelerate repair of the NE. BROX rebalances excessive cytoskeletal forces in cells experiencing NE instability to promote effective NERDI repair. In summary, BROX coordinates mechanoregulation with membrane remodelling to maintain nuclear-cytoplasmic compartmentalisation and genomic stability.

 

Lucia Prieto-Godino

Evolution of olfactory circuits in Drosophilid: From sensory periphery to central networks.

Sensory systems encode the world around us to guide context-dependent appropriate behaviours that are often species-specific. This must involve evolutionary changes in the way that sensory systems extract environmental features and/or in the downstream sensory-motor transformations implemented. However, we still know little about how evolution shapes neural circuits. We address these fundamental questions using as models the olfactory systems of different fly species, some of which are vectors for devastating diseases. We employ a multidisciplinary approach, including field work, the development of genetic tools across species, fast volumetric calcium imaging, single cell transcriptomics and comparative connectomics. I will discuss the progress we have made in our efforts to understand how evolution tinkers neural circuits as animals adapt to different environments.

 

Sophie Martin

Cell patterning by secretion-induced membrane flows, and other membrane events

My lab is interested in understanding fundamental principles of cellular organization and patterning, for which we mainly use the simple fission yeast eukaryotic model system. I will present two short stories that illustrate our recent insights into the organisation of the plasma membrane. I will first describe our discovery of membrane flows from sites of secretion. This finding stems from a serendipitous observation made during optogenetic manipulation. In back-and-forth mathematical simulations and experimental validation with synthetic probes, we found that a concentrated zone of exocytosis within a broader zone of endocytosis causes membrane flows leading to local depletion of membrane-associated proteins. Depletion strongly depends on rates of protein diffusion and membrane detachment, which may be regulated through complex formation. I will discuss how the phenomenon may be exploited by endogenous proteins for cellular patterning. In the second part, I will present our current work on cell-cell fusion, which is essential during sexual reproduction for the formation of the zygote. Cell fusion relies on the formation of a dedicated formin-nucleated actin structure called the fusion focus, which serves to concentrate the delivery of myosin-driven secretory vesicles for local cell wall digestion at the site of gamete contact. We collected a large correlative light-electron microscopy (CLEM) dataset of the fusion site, which revealed unexpected membrane asymmetries between the two gametes. Functional analyses suggest that these asymmetries are driven by unbalanced exo- and endocytic activities and differences in turgor pressure, which are required to promote the fusion process.

 

Sara Sdelci

The interaction between LOXL2 and BRD4 short isoform drives the expression of DREAM target genes in triple-negative breast cancer

Triple-negative breast cancer is a very aggressive cancer for which there is no targeted therapy. Additionally, this type of cancer very often develops resistance to treatment and becomes able to metastasize. One strategy to circumvent the insurgence of anticancer drug resistance is the development of efficient combinatorial approaches targeting multiple key cancer proteins. Recently, it has been shown that the inhibition of BRD4 and LOXL2 independently arrests breast cancer proliferation, having a more pronounced effect on the triple-negative subtype. Therefore, we combined those treatments to investigate their synergy potential. We discovered that the simultaneous inhibition of LOXL2 and BRD4 effectively reduces cancer cell growth in vitro. To our surprise, we revealed that the two proteins, which we initially thought to be completely unrelated, interact in the nuclear environment. In particular, the short isoform of BRD4 interacts with LOXL2 to promote the expression of DREAM target genes and sustain cell proliferation. Indeed, the inhibition or downregulation of LOXL2 induces the downregulation of DREAM target genes, cell cycle arrest, and loss of BRD4 transcriptional foci. Finally, we explored the synergy in vivo, either xenografting a triple-negative breast cancer cell line or a patient-derived triple-negative breast cancer sample into mice. Both approaches showed that the simultaneous inhibition of BRD4 and LOXL2 impairs tumor proliferation better than the single treatments. Overall our results indicate that the interaction between LOXL2 and BRD4 short isoform is fundamental for the proliferation of triple-negative breast cancer and that the simultaneous inhibition of both proteins holds potential for the treatment of this lethal disease.

 

Caroline Uhler

Causality, Perturbations, Gene Regulation, and Drug Repurposing

An exciting opportunity at the intersection of single-cell biology and machine learning stems from the growing availability of large-scale perturbational data (drugs, knockouts, overexpression, etc.). I will present a framework based on causality and autoencoders that can integrate observational and perturbational data and discuss applications to learning gene regulatory networks as well as predicting the effect of new perturbations. We end by discussing how such a framework can be applied for drug repurposing in the current COVID-19 crisis.

 

Alfonso Martinez Arias

Embryos, gastruloids and the Turing conjecture

The development of an organism has its roots in the process of embryogenesis, a complex sequence of coordinated patterns of gene expression and cell movements and reorganizations that create and elaborate the body plan. In his 1952 classic paper on “The chemical basis of morphogenesis’ (PMID: 2185858) Alan Turing suggested that this complexity results from the interaction between two modules: a chemical and a mechanical and that the way they are woven within each other creates a challenge for understanding.  In his study Turing restricted himself to investigate the chemical one.

Over the last few years, we have developed an experimental system for the study of early embryogenesis that we call ‘gastruloids’. This system, based on embryonic stem cells, reveals instances of uncoupling of the mechanical and the chemical modules thus opening the possibility to analyze their interaction experimentally.

I will introduce the gastruloid system and show how it can be used to reveal principles of multicellular organization. I will also speculate on some evolutionary implications that they pose.

Reference: Steventon, B., Busby, L. and Martinez Arias, A. (2021) Establishment of the vertebrate body plan: Rethinking gastrulation through stem cell models of early embryogenesis. Developmental Cell PMID: 34520764

 

Vicent Pelechano

Dissecting gene expression with genomics, from transcriptional memory to co-translational mRNA decay

RNA abundance is controlled by the balance between its synthesis and decay. Although most research is geared towards transcription; RNA degradation is also key to control final mRNA abundance, modulate gene expression kinetics and thus control protein production. First, I will discuss the relevance of RNA degradation during the dynamic remodelling of gene expression associated to transcriptional memory. Transcriptional memory is the process by which a gene previously exposed to a stimulus is primed for its reactivation. I will show how, in addition to well known chromatin factors, modulation of mRNA degradation also contributes to this process.  Next, I will focus on the crosstalk between ribosome dynamics and mRNA degradation.  We have previously shown that during 5’-3’co-translational decay, the degradation machinery follows the last translating ribosome producing a genome-wide footprint of its position. I will describe how our lab is investigating this process also in prokaryotes with divergent RNA degradation strategies. Finally, I will show how the study of the metadegradome enables the investigation of fast, species-specific, post-transcriptional responses to environmental and chemical perturbations in unculturable microbial communities.

 

 

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