Skip to main content
2019 -
Long-Term Fellowships - LTF

Saturating mutagenesis of the mitochondrial genome in search for critical cis-regulatory elements

DAVIDI Dan (ISRAEL)

Department of Genetics - Harvard Medical School - Boston - USA

CHURCHMAN L. Stirling (Host supervisor)

A plausible explanation for why mitochondria have their own DNA (mtDNA) is to ensure colocalization of redox-genes and redox-regulation to the same membrane-bound organelle. While this distributed control system seems logical, very little is known about how such autonomous regulation takes place. A variety of methods that are widely applicable to study genomes fail to work on mtDNA, and sequence-to-function mapping of the mitochondrial genome is missing. I plan to create a modified, hypermutating DNA polymerase gamma (polG), the designated mtDNA replicase. polG is encoded in the nuclear genome and can therefore be easily manipulated. Hypermutator polG will be integrated into the nuclear genome of S. cerevisiae, which will introduce mutations in mtDNA without altering the nuclear genome. I will then use selection assays followed by next generation sequencing to study the ability of mtDNA yeast variants to adapt to respiratory conditions. Such experiment will highlight regulatory hotspots in mtDNA that will be mechanistically evaluated using genome-wide methods like native elongating transcript sequencing (NET-seq) and mitochondrial ribosome profiling that are the ‘bread and butter’ of the Churchman lab. Clear view of the fitness landscape associated with mtDNA will inform research into many deep questions in mitochondrial biology, ranging from ‘how selection shapes mitochondrial genomes?’ to ‘why do certain mtDNA mutations cause cancer?’.

2019 -
Long-Term Fellowships - LTF

Elucidation of Trypanosoma brucei dynamics and biophysical properties in the host adipose tissue

DE NIZ Mariana (MEXICO)

Department of Parasitology - Instituto de Medicina Molecular Joao Lobo Antunes - Lisbon - PORTUGAL

MIRANDA-FIGUEIREDO Luisa (Host supervisor)

Trypanosoma brucei is the causative agent of sleeping sickness. In the mammalian host, parasites exist in two major niches: the blood, and the brain. Recently, Dr. Figueiredo’s lab found a previously undiscovered third reservoir of parasites in the adipose tissue which were transcriptionally distinct from blood stream forms, and the genes upregulated included various markers relevant to parasite metabolism. My proposed work in Dr. Figueiredo’s lab is to implement in vivo imaging methods to a) investigate the parasite’s mechanisms of homing and crossing of the vascular endothelium into the adipose tissue, and to carefully define the adipose tissue niche that acts as reservoir for the parasites; and b) to elucidate host vasculature, and parasite factors involved in allowing such unique phenomenon, including generating parasite mutants deficient in adenylate cyclises, flagellar proteins, and mechano-sensing proteins among others. Using in vivo techniques and biophysical and molecular methods, I aim to investigate the biological significance of parasite residence in the adipose tissue – a location which could be clinically relevant for interventions in human and veterinary medicine.

2019 -
Grant Awardees - Program Grants

Regrowing the brain: evolution and mechanisms of seasonal reversible size changes in a mammal

DECHMANN Dina (SWITZERLAND)

Dept. of Migration and Immunoecology - Max Planck Institute for Ornithology - Radolfzell - GERMANY

DAVALOS Liliana (COLOMBIA)

Dept. of Ecology and Evolution - SUNY Stony Brook - Stony Brook - USA

NIELAND John (NETHERLANDS)

Dept. of Health Science and Technology - Aalborg University - Aalborg - DENMARK

Organisms need strategies to survive when conditions are hard. For mammals, winter is particularly difficult - they have to invest large amounts of energy into keeping warm, while food availability is low. For this reason, many mammals migrate or hibernate. However, what to do if you are too small to migrate long distance, burn your energy fast, and cannot hibernate? The common shrew is such a mammal and has evolved an astonishing strategy: each individual shrinks in winter by up to 20% and then regrows in the spring by about 13%. This size change, thought to allow shrews to survive on fewer resources because of the smaller size and linked lower energy requirements, include not just overall size, but specifically organs that do not usually change size in fully grown animals, such as the brain, heart and liver.
The process of neurological degeneration and regeneration is of great interest, since many central nervous system diseases (e.g., Alzheimer’s, multiple sclerosis) involve degeneration, but ongoing research for therapies to reverse this process has been of limited success. As one of only a few recorded examples of mammalian brain regeneration, understanding how the shrew regrows its brain can accelerate research that leads to future therapies.
To answer the question of how the shrew shrinks and then regrows its brain, we will establish this unusual species as a new model, by studying the biological, molecular, biochemical and genetic processes behind this reversible size change. Besides establishing a database of information that can be mined and researched in years to come to discover the pathways that generate this cycle in the shrew, we will test a metabolic model of neurological change by artificially blocking molecular access to fats. Thus, the cross-disciplinary study of this wintering adaptation may help us understand more about regeneration in mammals in general, and the brain in particular.

2019 -
Cross Disciplinary Fellowships - CDF

The microscale biophysics of toxin dispersion during harmful algal blooms

DHAR Jayabrata (INDIA)

Physics and Materials Science Research Unit - University of Luxembourg - Luxembourg - LUXEMBOURG

SENGUPTA Anupam (Host supervisor)

Harmful algal blooms (HABs) have been long studied in marine and fresh water environments, yet most research to date has focused at the bulk scale. Despite the well-documented toxic ramifications of HABs on vertebrates and mammals, including humans, we still lack a biophysical understanding of the mechanisms by which toxins disperse during a bloom event. Using a combination of experiments and modelling, in this project I will explore the physico-chemical interplay underlying the release and transport of toxins at the scale of the microorganism. Towards this I will develop micro- and millifluidic experiments to generate ‘bloom-in-lab’ and visualize the dispersion of targeted toxins under three ecologically relevant cues: fluid flow, temperature and salinity. Specifically, I will study red-tide forming Heterosigma akashiwo, a globally distributed marine raphidophyte, known to release a range of toxins, including reactive oxygen-nitrogen species (RONS) during bloom conditions. Original data from high-speed and time-lapse microscopy on fluorescently labelled ‘target’ molecules will put forward first experimental quantifications of toxin release and transport under different micro-environmental cues, thereby informing a new mathematical model that will capture, at microscales, dispersion and auto-feedback dynamics during bloom events. Analysing the coupling between microbial biophysics, transport phenomena and biochemistry, this project will bring about a fundamental, mechanistic understanding of toxin transmission, and help develop accurate and comprehensive algorithms for predicting HAB formation, especially during the rapidly warming climate we encounter today.

2019 -
Career Development Awards

Elucidating the biological impact of precise genome editing in hematopoietic stem cells

DI MICCO Raffaella (ITALY)

San Raffaele Telethon Institute for Gene Therapy - Fondazione Centro San Raffaele - Milan - ITALY

Human medicine is on the verge of a new era where we face the possibility to precisely rewrite the genome to prevent, ameliorate and cure a wide range of immune-hematological diseases. Hematopoietic stem and progenitor cells (HSPC) have long been a preferred source for ex-vivo gene therapy, as gene correction in multipotent progenitors ensures a life-long supply of corrected progeny and polyclonal reconstitution of the bone marrow. Recently, programmable nucleases brought the possibility of genome editing (GE) within the reach of gene therapy by allowing locus-specific gene correction without the risk of aberrant transgene expression. However functional studies that accurately assess possible acute and long-lasting consequences of GE procedures in HSPC are needed to harness GE therapeutic potential. Indeed, despite recent advances in the generation of corrected HSPC by GE, the efficiency of the targeting process and the ability of edited cells to stably reconstitute the hematopoietic system upon transplantation remain limited, pointing to a loss of repopulating capacity of HSPC upon targeting. The goal of this project is to investigate the role of DNA damage response (DDR) pathways in GE strategies and uncover novel molecular players that could be exploited to increase the yield of long-term engrafting gene-edited HSPC. Our findings could be easily applied to gene correction strategies for a variety of inherited pathologies affecting the human immune-hematopoietic system and provide a foundation for more efficient modalities of editing HSPC at genomic sites of interest for both basic and translational research.

2019 -
Long-Term Fellowships - LTF

State-dependent routing of sensorimotor signals across areas of visual cortex

DRINNENBERG Antonia (GERMANY)

Department of Bioengineering - Stanford University - Stanford - USA

DEISSEROTH Karl (Host supervisor)

Areas of visual cortex integrate signals representing sensory input, ongoing motor actions, and internal states. While neurons in primary visual cortex (V1) were classically interpreted as feature detectors that signal the presence of a specific visual stimulus, recent evidence suggest that V1 circuits participate in the specific, topographical integration of sensorimotor signals. How sensory and sensorimotor computations are implemented in the circuitry of V1 and higher visual areas, and how these computations depend on the behavioral context, is unknown. I will combine novel circuit dissection tools, wide-field-of-view holographic stimulation, and virtual reality environments to approach these questions. I will selectively activate V1 ensembles with distinct functional properties during sensorimotor behavior using holographic stimulation and monitor the effects on the surrounding populations in V1 and higher visual areas. Furthermore, I will analyze the effects of holographic stimulation as a function of different behavioral parameters and during optogenetically induced variations in internal state. Finally, I will explore methods to target the expression of genetically encoded tools to distinct V1 ensembles, each with specific function during sensorimotor behavior, which will allow me to study if different ensembles are selectively connected to circuits throughout the brain, as well as to determine their selective impact on brain-wide dynamics. This project will shed new light onto the function of V1 during sensorimotor behavior, and yield fundamental insights into the mechanisms by which cortex can adapt its processing machinery to varying behavioral demands.

2019 -
Grant Awardees - Program Grants

Navigating the waters – A neural systems approach to spatial cognition in fish

ENGELMANN Jacob (GERMANY)

Dept. of Active Sensing - Bielefeld University - Bielefeld - GERMANY

SEGEV Ronen (ISRAEL)

Dept of Biomedical Engineering and Dept. of Life Sciences - Ben-Gurion University - Beer-Sheva - ISRAEL

BURT DE PERERA Theresa (UK)

Dept. of Zoology - University of Oxford - Oxford - UK

MUELLER Thomas (GERMANY)

Division of Biology / Mueller-lab - Kansas State University - Manhattan (Kansas) - USA

In 2014, the Nobel Prize in Physiology was awarded for the discovery of place and grid cells that process spatial cues in the mammalian hippocampal formation;, the key structure for both navigation and episodic memory1. Place and grid cells, and additional cell types form the central building blocks in the current circuit models of navigation in mammals. However, a cohesive picture of how these circuits compute space and enable navigation has not been achieved. In fact, emerging evidence suggest that these navigation circuits are highly diverse in cellular phenotypes and functionality; they do not only map aspects of space but also elements like sound, time, and reward. How neural systems of spatial cognition have evolved outside of the mammalian clade is not clear, and comparative studies are critically needed to gain insights to basic functional constraints and structural requirements underlying these neural circuits.
The international research team of four PIs proposes a broad comparative systems neurobiological approach using teleost fish for integrative studies on higher navigation circuits. These fish are ideal models because they have conquered diverse spatial ecologies and show highly specialized sensory adaptions. Also, their brains exhibit an overall lower complexity to mammals, and are highly accessible to experimental manipulation. To establish systematic research on teleostean spatial cognition, the project combines neuroethological, electrophysiological, neuroimaging, and computational methodologies. Introducing a powerful electrophysiological recording technology in freely-moving fish and generating long-needed anatomical atlas resources, the project analyzes four teleost species with differing spatial ecologies. The team will uncover how different sensory modalities like vision, perception of depth, and active electrolocation are integrated during spatial navigation tasks, thereby investigating how top-down mechanisms modulate sensory integration of spatial learning.
Finally, the team will test specific hypotheses developed in small-scaled laboratory setups in an unconstrained natural environment. Here, the group will measure the activity of neurons in freely moving fish that explore a coral reef habitat. This will be the first ever attempt to analyze brain activity underlying navigation in the wild. Altogether, the project will provide new perspectives on the evolution, function, and mechanism of memory systems in animal navigation.

2019 -
Long-Term Fellowships - LTF

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

ERNST Christina (GERMANY)

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 -
Grant Awardees - Young Investigator Grants

From DNA to K-fibers: probing centromere function in the genesis of age-related oocyte aneuploidy

FACHINETTI Daniele (ITALY)

Dept. of Subcellular Structure and Cellular Dynamics - Institut Curie - Paris - FRANCE

MOGESSIE Binyam (UK)

School of Biochemistry - University of Bristol - Bristol - UK

REDEMANN Stefanie (GERMANY)

Dept. of Molecular Physiology and Biological Physics - Center for Membrane & Cell Physiology - Charlottesville - USA

Cell division is a complex but fundamental life process. Among its many purposes, it is needed for a fertilized egg to develop into a human being, for our wounds to heal, for infections to clear and for our bodies to sustain life. Whenever a cell divides, its genetic information is duplicated and packaged into chromosomes which are then separated and equally distributed between the new daughter cells. For the newly formed cells and ultimately the body to be healthy, distribution of the chromosomes should be highly accurate. Accurate chromosome separation during cell division is driven by dynamic cellular cables that are connected to special chromosomal regions known as centromeres. Indeed, defects in centromere formation or function compromise chromosome separation and lead to daughter cells containing too many or too few chromosomes, a hallmark of cancerous cells.
When eggs are prepared for fertilization, a specialized form of cell division called meiosis separates the chromosomes. The accuracy of chromosome separation during meiosis determines whether a fertilized egg can develop into a healthy human being. Surprisingly, meiosis in humans and other mammals is highly prone to errors and often leads to eggs that contain the wrong number of chromosomes. Fertilization of such chromosomally abnormal eggs frequently leads to human embryo deaths and conditions such as Down’s syndrome. Complications arising from erroneous chromosome separation in eggs become even more frequent as women get older. Research in the field of meiosis has only scratched the surface of why chromosome separation in eggs is highly error-prone. Furthermore, the reasons behind the deterioration in the quality of this process as women get older largely remain unknown.
In this research proposal, we will test the hypothesis that defects in centromere function that accompany ageing may contribute to poor quality of eggs in older women. To achieve this, we will combine our unique but synergistic expertise in advanced light microscopy, genome editing and electron microscopy. Knowledge gained from this study will advance our understanding of why eggs of older women are often chromosomally abnormal. In the long-term, this work can potentially be exploited for treatments of human infertility.

2019 -
Long-Term Fellowships - LTF

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

FRIEDRICH Daniel (GERMANY)

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

FROEHLICH Fabian (GERMANY)

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

GEISSMANN Quentin (FRANCE)

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

GIBEAUX Romain (FRANCE)

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

GIRALDO SANCHEZ Diego (COLOMBIA)

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

GIZOWSKI Claire (CANADA)

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

GLASER Juliane (FRANCE)

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 -
Grant Awardees - Young Investigator Grants

From synapses to networks. Understanding mechanisms of fear generalization across brain scales

GREWE Benjamin F. (GERMANY)

Dept. of Information Technology and Electrical Engineering - Swiss Federal Institue of Technology (ETH) Zurich - Zurich - SWITZERLAND

ARRUDA-CARVALHO Maithe (BRAZIL)

Dept. of Psychology - University of Toronto - Scarborough - Toronto - CANADA

KHEIRBEK Mazen (USA)

Dept. of Psychiatry - University of California San Francisco - San Francisco - USA

A shared feature of many anxiety disorders is the overgeneralization of fear, the tendency to falsely link together events that have differing emotional significance. In the case of abnormal fear learning this can produce heightened levels of arousal and fear in situations that should be perceived as safe.
Previous studies indicate several distributed brain areas interacting with neuronal networks in the amygdala to modulate the fearful perception of diverse stimuli. It therefore remains largely unknown how changes in synaptic and cellular function (synaptic scale) can influence encoding of fearful stimuli in large cell networks (network scale) and how interaction between brain areas (global scale) finally leads to overgeneralized behavioral responses. Although a few studies have begun to examine neural substrates of fear generalization at the synaptic and network level, to date, no structured and integrated picture has been generated. This major gap exists because no study so far has been able to integrate experimental results across the different scales to generate a complete model of interactions that regulate fear generalization. As a consequence, new therapies and drugs to treat anxiety disorders emerge only slowly with no major discoveries in sight.
In this proposal, we aim to utilize a unique combination of expertise in neurophysiology, optogenetics and advanced brain imaging to study the mechanisms of fear generalization across spatial scales, ranging from synapses to individual neurons, to large-scale, distributed networks across the whole brain. For the first time we will investigate how local amygdalar networks regulate fear generalization within the context of their afferent signals emerging from global brain activity. To connect synaptic, network and global scales, we will develop new innovative technologies such as an fMRI compatible version of a miniaturized microscope for functional Ca2+ imaging to simultaneously monitor whole brain function and local network activity during fear generalization tests in mice. We will complement these studies with in vivo Ca2+ imaging, optogenetics, and ex vivo electrophysiology to identify the distributed inputs and local circuits in the amygdala that generate overgeneralized fear responses.
The goal of our interdisciplinary systems neuroscience/engineering approach is to provide a comprehensive understanding of the neural substrates that trigger overgeneralized fear, thereby generating a novel framework for how anxiety-related behaviors emerge across different brain scales.

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

HALLIN Johan (SWEDEN)

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.