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2019 -
Long-Term Fellowships - LTF

Expanding the regulatory role of human KRAB-zinc finger proteins by profiling their RNA interactome


Global Health Institute - EPFL - Lausanne - SWITZERLAND

TRONO Didier (Host supervisor)

Transposable elements (TEs) are important drivers of genome evolution with the potential to rewire transcriptional networks but require constant surveillance to minimise deleterious effects. Major players in the transcriptional regulation of TEs are KRAB domain-containing zinc finger proteins (KZFPs) that co-evolved in response to new TE invasions and constitute the largest family of transcription factors encoded by the human genome.
Recent views have shifted from a simple arms race between TEs and their host genomes towards a more complex domestication process. This can involve the rewiring of gene regulatory networks using TE-derived regulatory elements, co-option of TE-derived genes, but also the exaptation of KZFPs to acquire new regulatory functions after the interaction with their target TE has become obsolete.
Such newly adapted functions for KZFPs can be mediated by novel protein interactors but can also involve the binding to, and regulation of RNA molecules, as zinc finger domains are not limited to interactions with DNA. Indeed, many of the evolutionary conserved KZFPs show weaker interactions with the TE-silencing machinery and instead display unique protein interactomes that indicate an RNA-based functionality.
This proposal lays out the experimental strategy to systematically identify RNA-binding KZFPs in the human genome and profile their corresponding RNA interactomes to elucidate the underlying regulatory mechanism. Exaptation of KZFPs to function as RNA-binding proteins extends their role from transposon control to post-transcriptional regulation of protein-coding and non-coding RNA molecules, thus providing intriguing new layers of gene regulation.

2019 -
Long-Term Fellowships - LTF

Deciphering the molecular mechanisms of non-canonical translation orchestrating cell fate decisions


Department of Biological Chemistry and Molecular Pharmacology - Harvard Medical School - Boston - USA

D'SOUZA Victoria (Host supervisor)
WAGNER Gerhard (Host supervisor)

Non-canonical initiation of protein translation plays a central role during cellular stress, apoptosis and cell survival. Death-associated protein 5 (DAP5) acts as the major scaffolding initiation factor to promote cap-independent translation of cellular mRNAs such as p53, Bcl2, Apaf1 and XIAP. Potentially, translation of such transcripts can be initiated via internal ribosome entry sites (IRESs), an alternative to canonical cap-dependent translation. The structural and molecular mechanism of how DAP5 regulates IRES-driven translation is not understood. To resolve the inherent molecular processes, I will investigate IRES recognition by DAP5 in target mRNAs through novel NMR techniques, biophysical tools and mass spectrometry. My research is aimed to solve the first three-dimensional structure at atomic resolution of a cellular IRES along with its functional characterization. Based on this, the interaction between this IRES and DAP5 that is relevant for cell fate decisions will be studied structurally and biophysically. I will analyze not only the role of the structured MIF4G domain of DAP5, but also the so far unknown function of its disordered regions in IRES recognition. In order to shed light on regulatory principles of DAP5, I further aim to investigate structural effects on mRNA binding upon DAP5 phosphorylation. In a proteome-wide examination, I will identify additional factors of IRES-mediated translation to define a potential core complex associated with different mRNAs. My project thus comprehensively aims to decipher the mRNA recognition mechanism of DAP5 that controls IRES-driven, cap-independent translation linked to cell fate decisions.

2019 -
Long-Term Fellowships - LTF

Unraveling melanoma adaptive resistance through kinetic and statistical modeling


Department of Systems Biology - Harvard Medical School - Boston - USA

SORGER Peter K. (Host supervisor)

Adaptive resistance is an emergent phenomenon in melanoma cells that allows tumor cells to adapt and escape treatment through a change in signaling state. The complex interplay between transcriptional and post-transcriptional regulation that gives rise to adaptive resistance is in large parts poorly understood. To unravel the underlying molecular mechanisms, in silico approaches involving statistical or kinetic models have to complement experimental analysis. Statistical models are well-suited to identify unknown molecular mechanisms but cannot describe emergent phenomena. In contrast, kinetic models intrinsically describe emergent phenomena but are challenging to apply when the underlying molecular mechanisms are unknown.
In this project, I propose a novel, integrated, data-driven approach to unravel the molecular mechanisms that give rise to adaptive resistance in melanoma. The approach combines kinetic and statistical modeling to harness the benefits of both approaches. The statistical modeling will be used to derive biological hypothesis to construct and extend kinetic models in an unbiased, data-driven, automated fashion. This will render the construction of kinetic models less dependent on prior knowledge. The constructed kinetic model will be able to quantitatively describe emergence of adaptive resistance and provide insight into underlying molecular resistance mechanisms.

2019 -
Long-Term Fellowships - LTF

Manipulation of insect vector behaviour by the plant microbiome


Department of Microbiology and Immunology - University of British Columbia - Vancouver - CANADA

HANEY Cara (Host supervisor)

Plants are the primary producers in land ecosystems, a central position that give them a fundamental ecological importance. In the wild, plants interact with multiple organisms, including bacteria and insects, to form rich interconnected networks. In particular, plants are colonised by communities of microbes, including both beneficial and pathogenic bacteria. For these microorganisms, it is crucial to spread between plants, which they often do by recruiting herbivorous insects as vectors. Plant pathogens may even manipulate the behaviour of the insect that carries them. However, the underlying mechanisms and evolutionary dynamics of this important behavioural component of plant-insect-bacteria systems remain unknown.

My work will address how bacteria attract and alter the behaviour of their insect vectors by combining three fields of biology: plant physiology, insect behaviour and bacterial genomics. This project follows two independent questions: 1) how pathogenic bacteria attract insect vectors and 2) whether bacteria that have colonized a vector can manipulate vector behaviour. To address these questions, I will
use the Sacptomyza-Arabidopsis-Pseudomonas system as a model of bacteria-facilitated herbivory
and build high-throughput experimental assays to score the behaviour of the drosophilid Scaptomyza. This quantitative approach will allow me to compare the effect of dozens of bacterial stains on the behaviour of their vector and ultimately to find the bacterial genes required for vector recruitment and manipulation. This approach could to transform a largely descriptive area of plant-insect-bacterial interactions into a high-throughput and mechanistic field.

2019 -
Career Development Awards

Understanding the structural basis regulating spindle size and architecture


Institute of Genetics and Development of Rennes - University of Rennes 1 - CNRS - Rennes - FRANCE

Mitosis is key to the cell cycle, as it guarantees the accurate segregation of replicated chromosomes to daughter cells. This process relies on the mitotic spindle, a microtubule-based, dynamic, and bipolar structure. Spindle morphology varies greatly among species and cells to optimise its function. Size and architecture, in particular, are both essential for accurate chromosome segregation, cell division and cytokinesis. However, despite decades of study and the investigation of hundreds of proteins involved in spindle assembly, it remains unclear how spindle microtubule subpopulations organise into complex assemblies. Especially, how correct spindle morphometrics, at both the size and architectural levels, are established is poorly understood. Using the egg extracts of two Xenopus species of different spindle sizes and architectures, X. laevis and X. tropicalis, we will reconstruct microtubule structures assembled independently from the two major organising sites that contribute to spindle assembly, the spindle poles and chromatin. By combining cutting-edge fluorescence microscopy and electron tomography analyses, we aim to reveal the dynamic and ultrastructural bases of spindle substructure size and architecture. Our goal is then to extract quantitative parameters and combine them into physically realistic simulations to decipher the biophysical basis of the different architectures and scaling properties, and ultimately their implication for the regulation of spindle morphology. Altogether, this study at the frontier between cell biology and biophysics will not only unravel key mechanisms of microtubule organisation but also fundamental principles of spindle assembly.

2019 -
Long-Term Fellowships - LTF

Neuromodulatory networks controlling mosquito attraction to humans


Department of Molecular Microbiology and Immunology - Johns Hopkins University - Baltimore - USA

MCMENIMAN Conor (Host supervisor)

Mosquitoes rely on their exquisitely tuned sense of smell to efficiently home in on humans to blood feed. This epidemiologically important behavior is intricately gated by the internal physiological state of the mosquito. For instance, upon starvation the African malaria mosquito Anopheles gambiae reflexively exhibits heightened attraction towards human scent. Such state-dependent shifts in sensory perception are often evoked by neuromodulation of olfactory circuitry mediating attraction to food. Here, I propose to apply genome engineering coupled with multiphoton imaging in the mosquito nervous system to identify key olfactory circuits and neuromodulatory networks that control An. gambiae attraction to humans. To achieve this goal, I will initially characterize how whole human scent and its constituent odorants are represented in the primary olfactory processing center of the An. gambiae brain, the antennal lobes. Subsequently, I will determine if this pattern of neural representation is altered during fed and fasted states, as well as stages of malaria parasite infection previously shown to influence olfactory behavior in this mosquito species. Finally, I will evaluate a potential role for neuropeptide signaling in altering synaptic physiology during state-dependent changes in mosquito food search behavior.

2019 -
Long-Term Fellowships - LTF

The molecular and cellular mechanisms underlying thermodetection by vagal sensory neurons


Department of Physiology - UC San Francisco - San Francisco - USA

KNIGHT Zachary (Host supervisor)

Life requires that the brain accurately measure both internal (body core) and external (environmental) temperature. Environmental temperature detection allows animals to find suitable thermal climes and to perceive and learn to avoid painful stimuli. The mechanisms of environmental temperature detection are increasingly well understood, however the mechanisms by which the brain measures internal body temperature remain poorly defined. The vagus nerve is the dominant sensory system that monitors the state of the viscera, and vagal afferents are critical for commanding unconscious processes essential to life, such as keeping heart rate constant and controlling food digestion. But how the vagus nerve contributes to thermoregulation remains a mystery, and almost nothing is known about the specific molecules, cells, and pathways by which these afferents can trigger physiological and behavioural responses to temperature. I propose to identify the molecular and cellular mechanisms underlying thermodetection by vagal afferents innervating the gastrointestinal tract (GI) including the oesophagus, stomach and intestine. I will determine the molecular identity of vagal afferent cell types that measure core body temperature, determine the neurochemical signals that these thermosensitive vagal neurons use to communicate with the brain and test the hypothesis that these vagal cell types are essential for regulating temperature-dependent autonomic and behavioural functions in awake, behaving animals.

2019 -
Long-Term Fellowships - LTF

The role of MusD transposable elements in the 3D regulation of the mammalian genome


Development and Disease Group - MPI for Molecular Genetics - Berlin - GERMANY

MUNDLOS Stefan (Host supervisor)

The redundant and long-distance activity of regulatory sequences such as enhancers controls tissue-specific gene expression during development. Enhancers are brought in proximity with their target genes through the 3D folding of chromatin in domains of specific interaction. Several factors including CTCF have been shown to be important for this process, but the role of repetitive sequences remains unknown. Here, I propose to investigate the impact of transposable elements (TEs) on gene regulation and the 3D organization of the genome. Focusing on one type of evolutionary young retrotransposon in mice, the MusD elements, I will address this question through three lines of research. (1) a locus-specific approach focused on a model of TE-associated limb malformation to investigate the impact on 3D chromatin folding and gene expression; (2) a genome-wide approach to gain insight into the impact of active TEs on gene regulation and (3) a targeted approach to identify a TE trans-acting factor responsible for silencing such elements. This will be achieved by combining cutting-edge genomic technologies with mouse embryo analysis and the generation of mutants through CRISPR/Cas9. These investigations are expected to reveal specific mechanisms by which transposable elements are able to influence chromatin folding and the expression of developmental genes. My work will shed light on the role of repetitive sequences in shaping the 3D architecture of the mammalian genomes thereby bringing new mechanistic insight into basic mechanisms of gene regulation and retrotransposon biology.

2019 -
Long-Term Fellowships - LTF

Principles and mechanisms of intergroup contests: understanding social evolution

GREEN Patrick (USA)

Department of Biosciences - University of Exeter - Penryn - UK

CANT Mike (Host supervisor)

The evolution of animal sociality has been driven, in part, by the balance of cooperation and conflict. Extensive studies of dyadic (one-on-one) conflicts across taxa have revealed how opponents achieve safe resolution by assessing competitive ability. While conflicts between groups of social animals are equally important, little is known about how competing groups assess ability. Studying intergroup assessment can reveal principles that extend across taxa, influencing our understanding of the evolution of sociality.
I will adapt the theoretical and experimental framework of dyadic assessment to test principles of intergroup assessment. I will first use a database of over 600 banded mongoose contests to test central components of conflict dynamics: how group composition predicts competitive success, how territory ownership confers an advantage, and if groups of similar ability have more dangerous contests. I will also experimentally test how banded mongooses use scent markings and collective “war cry” calls in intergroup assessment, including if and how “leaders” of conflicts differ from other group members. Finally, working in the extremely tractable wood ant system, I will use automated tracking and network analysis to test how individual-level behavioural variation influences overall group contest dynamics.
This project integrates big data, behavioural ecology, and state-of-the-art individual tracking to reveal principles of intergroup assessment that extend across taxa and levels of social organisation. The outcomes of this work can influence research in fields like animal contests, social evolution, and human psychology, among others.

2019 -
Long-Term Fellowships - LTF

Regulating mammalian mitochondrial homeostasis

GUNA Alina-Ioana (CANADA)

Department of Cellular and Molecular Pharmacology - UC San Francisco - San Francisco - USA

WEISSMAN Jonathan (Host supervisor)

Mitochondria are dynamic, multifunctional organelles that are a defining feature of eukaryotic cells. Maintaining mitochondrial homeostasis is essential for normal cellular and organismal physiology. Mammalian cells have roughly ~1,500 mitochondrial proteins, however the vast majority are encoded in the nuclear genome. Therefore, in response to stress, mitochondria must signal their internal states to the nucleus, which can mount a compensatory transcriptional response. Despite the fundamental importance of mitochondrial regulation, the full range of perturbations that disrupt homeostasis, the subsequent signalling cascades and the resultant nuclear responses remain poorly defined in higher eukaryotes. One consequence of mitochondrial stress is the activation of the integrated stress response (ISR), though the mechanism of this remains obscure. I propose to address these aspects of mitochondrial homeostasis in human cells using complementary genetic and biochemical strategies. i) First, I will use a CRISPRi screen to identify factors involved in activation of the ISR. ii) I will use Perturb-seq technology to objectively and systematically establish the full spectrum of stress induced transcriptional responses needed to maintain mitochondrial homeostasis. I will then use the approaches in (i) to explore the exact mechanism for key responses. iii) Finally, I will dissect the role of a new factor TMA7, identified through a previous genetic screen aimed at uncovering genes that sensitize mitochondria to proteotoxic stress. In all cases, the ultimate goal is to delve into the biochemical mechanism of how promising hits are involved in maintaining mitochondrial homeostasis.

2019 -
Long-Term Fellowships - LTF

A forward systems biology approach to investigate the origins and fitness effects of de novo proteins


Département de Biologie - Institut de Biologie Intégrative et des Systèmes - Québec - CANADA

LANDRY Christian (Host supervisor)

Proteins emerging from previously non-coding DNA regions are becoming increasingly appreciated as an important path to creating completely novel functions. However, their path of emergence is very poorly characterized. Comparative genomics studies are finding numerous genes that have emerged from non-coding sequences, providing deep insight into gene evolution. However, these studies provide no insight into the transition from non-coding to coding because these genes have already been shaped by selection. For instance, de novo gene emergence could be frequent but mostly deleterious, or rare but mostly advantageous. In our project, we propose to go beyond classical comparative genomics and force novel proteins to emerge to measure their fitness effects and biochemical properties, and establish the relationship between the two. We will measure the fitness effect of these proteins, confirm their existence and localization, as well as their propensity to interact with other proteins. We will identify protein properties such as length and intrinsic disorder that define the fitness effects and thus the likelihood for a novel protein to emerge. Because many of these biochemical properties are largely defined by nucleotide sequences, our findings will lead to models that directly link de novo gene sequences to fitness effects, allowing us to model gene emergence from sequence composition alone. This will be the first project that is poised to answer the major question of how novel proteins can emerge from previously non-coding sequences.

2019 -
Cross Disciplinary Fellowships - CDF

Deep-tissue voltage imaging in the intact mouse brain


Applied and Engineering Physics - Cornell University - Ithaca - USA

XU Chris (Host supervisor)

Understanding the cellular and molecular mechanisms on memory formation is one of the most important topics in life science and will be highly effective for development of remedies of memory disorders such as Alzheimer’s diseases and dementia. The modification mechanism of the neural network in the brain is a key factor for memory formation, but its understanding is not sufficient yet. The main reason is that direct observation of the neural network modification during memory formation in intact animal brains is still very difficult today. Voltage imaging, which enables direct observation of membrane potential, is a powerful technique for visualization of neural activities ex vivo. In contrast, in vivo voltage imaging in intact mouse brain is highly challenging despite the importance. The difficulty is derived mainly from the following requirements; (i) high signal-to-background ratio in the deep brain of the intact mouse, and (ii) high temporal resolution (<5 ms) for the voltage imaging. In the proposed study, three-photon excitation with near-infrared femtosecond laser will be applied to achieve the condition (i). Three-photon excitation is highly effective because NIR (1300-1700 nm) shows very low scattering from tissues, thus high signal-to-background ratio will be attained. To achieve (ii), an adaptive femtosecond laser source will be applied, making the laser light irradiated only to the regions of interest. The proposed in vivo voltage imaging will be applied to monitor neural network modification in the intact mouse brain during memory formation.

2019 -
Long-Term Fellowships - LTF

Mechanisms underlying distortions in the neural code induced by sensorineural hearing loss


Ear Institute - University College London - London - UK

LESICA Nicholas (Host supervisor)

Hearing loss, ranging from mild to severe, is a detrimental condition linked to decreases in quality of life for those affected. The causes of hearing loss have been extensively studied previously, and few options are available in rescuing hearing loss. Hearing aids have become the standard for treating hearing loss; however, they have only been partially successful due to their limitations when processing sounds in noisy environments. This is due to the fact that hearing loss causes complex distortions in neural activity patterns of the auditory system, which are not fully understood to date. The aim of this project is to identify key features of the neural code for speech that are distorted by hearing loss, and as a result, be able to assess the ability of current hearing aids to correct these distortions. Using recent developments in technology, we will use custom designed multi-channel electrodes to perform large-scale recordings in the inferior colliculus (IC) of the Mongolian gerbil. We will perform these recordings in both anaesthetized as well as awake-behaving gerbils under control and induced hearing loss conditions. We will then assess the neural activity patterns of IC neurons and determine the key distortions caused by hearing loss under differential stimulus conditions mimicking noisy situations. Standard analysis of coherence of speech information will be assessed to understand to what extent certain sounds become distorted under hearing loss. The results of this study will reveal novel insights into how hearing loss creates distortions in the neural code along the auditory pathway, and provide ideas for the efficacy of current and future hearing aids.

2019 -
Long-Term Fellowships - LTF

Investigating the role of transposable elements in 3D genome organisation in vivo


Institute of Epigenetics and Stem Cells - Helmholtz Zentrum München - München - GERMANY

TORRES-PADILLA Maria Elena (Host supervisor)

After fertilisation in the early embryo, the epigenetic reprogramming of heterochromatin is thought to be necessary for development. Notwithstanding, the mechanisms driving the de novo formation of heterochromatin are unclear. In somatic cells, transposable elements (TE) are largely heterochromatic and transcriptionally inert. However in the pre-implantation embryo many TE families are highly expressed. Recently, the expression of several TE families has been shown to be necessary for development. However, how TEs drive the developmental program mechanistically is unknown. I propose that their expression is essential for the establishment of heterochromatin, through the formation of long-range chromatin interactions during development. To address this hypothesis, I will establish a targeted DAM-ID protocol to map the genome-wide long-range DNA interactions formed by TE families in vivo, dynamically throughout development. I will develop novel technologies to analyse their chromatin composition and nuclear organisation to uncover the relationship between TE organisation and the establishment of heterochromatin and higher order chromatin structures. To determine the function of TE expression in development, I will perturb their expression and chromatin composition and investigate the ensuing effect on their higher-order organisation, nuclear localisation, and more broadly on heterochromatin formation and development. Finally, I will use the datasets generated in this study to generate a comprehensive model on the mechanisms driving higher order chromatin formation at TEs, and how they influence the local and higher order chromatin architecture in development.

2019 -
Long-Term Fellowships - LTF

Dissecting functional long non-coding RNAs and their working mechanisms


Department of Pathology - Stanford University - Stanford - USA

FIRE Andrew z. (Host supervisor)

It has been well established that eukaryotic genomes produce thousands of short and long non-coding RNAs. Many studies have uncovered the biosynthesis, processing, and functions of small non-coding RNAs. However, whether long non-coding RNAs (lncRNAs) are functional molecules or not has not been clear. Although supporting evidence of functional lncRNAs have been accumulated for the last decade, the working mechanisms of functional lncRNAs are still largely unknown. In this proposal, I aim to 1) identify functional lncRNAs in C. elegans by performing in-depth phenotyping with a large collection of lncRNA knockout mutants, and 2) characterize working mechanisms of the functional lncRNAs by using unbiased genetic and biochemical screen approaches. This study will help unveil mechanisms by which lncRNAs exert functions, and provide insights into how and why eukaryotic genomes contain a large number of the non-coding genetic elements that produce lncRNAs.

2019 -
Long-Term Fellowships - LTF

Mechanistic investigation into the driving forces of sensorimotor learning in the visual cortex

JORDAN Rebecca (UK)

Department of Neurobiology - FMI Basel - Basel - SWITZERLAND

KELLER Georg (Host supervisor)

How our brain learns the relationships between movements and the associated sensory feedback is an important question facing neuroscience. Since such sensorimotor relationships are subject to change, sensorimotor learning is crucial for the development of flexible sensory-guided behaviours. One elegant potential solution to this problem would be that the brain generates an internal model of the world that is used to make predictions about the sensory feedback given a certain motor output. Discrepancies between predicted and actual feedback could then be represented as prediction errors, which in turn could be used to update the internal model used to make the predictions. Recent experiments in which sensory feedback was manipulated during movement have revealed neural responses consistent with prediction errors in primary sensory areas of cortex. In primary visual cortex, these responses have been shown to depend on the precise tuning between visual and motor input that is learned with experience. However, both the mechanisms underlying this learning, and the effect of the error-like responses are unknown. In this project, I propose experiments employing a range of techniques, including calcium imaging, in vivo whole cell patching, and optogenetics in order to investigate the driving forces of sensorimotor learning. I will manipulate the activity of single cells in the visual cortex and probe neuromodulatory plasticity signals during visuomotor learning. This will provide a fundamental mechanistic insight into how sensorimotor learning takes place.

2019 -
Long-Term Fellowships - LTF

Explaining evolutionary divergences in epithelial morphogenesis through cell biological innovations


Centre for Organismal Studies - University of Heidelberg - Heidelberg - GERMANY

LEMKE Steffen (Host supervisor)

During early embryonic morphogenesis, naïve epithelia undergo structural changes like bending, folding, stretching, convergent-extension, growth, or even epithelial-to-mesenchymal transitions. Various species show evolutionary divergences in these morphogenetic processes. I propose that such differences in epithelial morphogenesis depend, in part, on physical parameters like tissue area, cell packing, cell aspect ratio, and the pliability of mechanical connectivity between cells. In fly embryos, the blastoderm epithelium undergoes morphogenesis after being defined from a zygote syncytium, in a process called cellularization. The process of cellularization is well described, very stereotypical, and the genetic and molecular players establishing basic cellular properties are known in Drosophila.

I will take advantage of natural diversity that accumulated over 250 million years of fly evolution and resulted in highly different blastoderm epithelia that vary substantially in tissue area, cell packing and cell aspect ratio. The host lab maintains lab cultures for 10+ fly species, including mosquito-related midges and moth flies, scuttle and hover flies, and various drosophilid species, which collectively sample a broad range of natural diversity in the insect order. I propose to compare cell properties and tissue morphogenetic behavior of the embryonic blastoderm in these species, with the aim to identify key genetic innovations underlying the origin of novel tissue properties and divergence in morphogenesis. I will further test how the introduction of these novel genetic elements into more rudimentary systems consequently changes cell properties and epithelial morphogenesis.

2019 -
Long-Term Fellowships - LTF

Mechanistic and structural studies of the RNA m6A writer machinery


Department of Biochemistry - University of Zurich - Zurich - SWITZERLAND

JINEK Martin (Host supervisor)

Post-transcriptional mRNA modifications have emerged as important mechanisms in eukaryotic gene expression control. The most abundant epitranscriptomic mark, N6-adenosine methylation (m6A), affects the processing, translation, and degradation of mRNAs and thus is involved in diverse biological processes including stem cell self-renewal, sex determination, and immunity. Uncovering the m6A molecular mechanisms is crucial to understand its function in gene regulation and shed light on its implicated roles in cancers and psychiatric disorders. Numerous studies have revealed the cellular m6A landscape, defined by writer and eraser enzymes and interpreted by reader proteins. Nevertheless, specific aspects of the m6A pathway, including how mRNAs are chosen for methylation, are not fully understood. Although the m6A mark occurs within a consensus sequence, not all such sites are modified in the transcriptome. It is unclear how the core METTL3/METTL14 methyltransferase complex recognizes its RNA substrates and how additional factors, such as the recently identified MACOM complex, contribute to this mechanism. To address these questions, the proposed research will aim to: (i) characterise the substrate RNA recognition mechanism of the METTL3/METTL14 complex, (ii) define the molecular architecture of the MACOM complex, and (iii) determine the structural and functional links between METTL3/METTL14 and additional m6A writer factors. To achieve these goals, I will combine structural biology with biochemical, biophysical, and functional cell-based assays. Together, these studies will provide fundamental insights into the molecular mechanisms of m6A in epitranscriptomic gene regulation.

2019 -
Long-Term Fellowships - LTF

Unraveling an interdependency between metabolic cluster for the homeostasis of cellular ATP and Pi


Department of Biochemistry - University of Lausanne - Epalinges - SWITZERLAND

MAYER Andreas (Host supervisor)

Cells face a phosphate challenge. Growth requires a minimal concentration of this limiting resource because intracellular phosphate (Pi) is a compound of nucleic acids modifies most cellular proteins, and is crucial to maintain the cellular ATP/ADP balance. At the same time, cytosolic Pi may not rise much, because elevated cytosolic Pi can stall metabolism. It reduces the free energy that nucleotide triphosphate hydrolysis can provide to drive energetically unfavorable reactions. Cells should hence coordinate their systems for uptake, export and storage of Pi in order to strike the delicate balance between the biosynthetic requirements for Pi and the risks of elevated cytoplasmic Pi. Exploring the signaling mechanisms that guarantee Pi homeostasis is challenging, because intracellular Pi is tightly linked to other metabolites: ATP/ADP, inositol pyrophosphates, and inorganic polyphosphate. These four metabolite classes influence each other's concentrations. I want to dissect this apparently conserved "metabolic cluster" and render the signaling pathways that regulate it accessible. To this end, I will create tools and methods to uncouple these parameters and fix one or several of them to an invariant value. This will allow me to "isolate" the signaling pathways responsible for the homeostasis of these essential parameters and possibly elucidate novel regulatory loops of Pi and energy metabolism.

2019 -
Long-Term Fellowships - LTF

Dissecting the role of intestinal lymphatics in bacteria-derived metabolite transport and signaling


Department of Fundamental Oncology - University of Lausanne - Lausanne - SWITZERLAND

PETROVA Tatiana (Host supervisor)

The gut is a dynamic and complex organ characterized by constant epithelium turnover and crosstalk among various cell types and the microbiota, the ecological community of commensal and, sometimes, pathogenic microorganisms. Changes in the composition of the gut microbiota have been connected to multiple aspects of host physiology and human disease, however relatively few microbe-host interactions have been defined at the level of molecular mechanisms. Here I propose to investigate the role of intestinal lymphatic vasculature in bacteria-derived metabolite transport and signaling. Intestine is richly supplied by lymphatic vessels. Known functions of lymphatic vessels of the gut include dietary fat absorption and transport of immune cells and dietary antigens to regulate tolerance or immune responses. To date, nothing is known about the microbiota-derived metabolites transported by intestinal lymph flow through lymphatic vessels and the role of those metabolites in body homeostasis. My main goal will be to use unbiased metabolomics and other systems biology approaches in combination with genetic animal models to characterize lymph bacteria-derived and host metabolomes and to establish an impact of extrinsic or intrinsic factors such as diet and lymphatic function on production and distribution of such metabolites in the body. I anticipate that the project will uncover previously unknown roles of intestinal lymphatic vasculature and bacterial metabolite signaling in specific target cell populations.