FMI

In the FMI Young Investigator Seminar Series, we are inviting postdocs and young group leaders to share their work and discuss with the FMI community.

The talk is followed by an informal (open mic) group chat (Virtual Pub).

FMI researchers have also the chance to chat 1-1 with the invited speakers.

If you would like to register for 1-1 meeting with any of the speakers or if you have any questions, please write to us at : yiss@fmi.ch

Zoom links will be distributed via the FMI mailing lists.

Organizers: Nikolas Karalis, Alicia Michael, Postdoc Representatives

Current/future events
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Current and future events

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Date Speaker Title and description
June 18, 2021 - 15:00

Björn Grüning
University of Freiburg
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Democratizing big data analysis with Conda, Containers and Galaxy

Abstract

Projects like ENCODE, HCA or the 1+MG project have been generating and will generate PetaBytes of data that are freely accessible to all researchers. This is posing completely new challenges to our community but also a lot of opportunities.

In this talk we will cover the bioinformatic advantages over the last years, with a specific focus on Conda, Containers and the Galaxy framework. We will explain how those projects and freely available global compute infrastructures enables scalable and reproducible science to cope with the mentioned challenges.

June 25, 2021 - 15:00

Yingxue Wang
Max Planck Institute Florida
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Generation mechanisms of memory-related internal sequences in the hippocampal CA1 region

Abstract

Episodic memory is a unique type of memory that enables us to mentally re-experience specific episodes in the past.

During memory encoding, a continuous stream of experience is segmented into episodes each of which encodes a temporally organized sequence of events.

Memory-related sequential neuronal activity patterns have been identified in the hippocampus, a brain region essential for episodic memory formation.

However, it is unclear how the hippocampus can parse behavior-level boundaries and encode individual segments of experience.

Here, we investigate the circuit-level mechanism that slices experience into units such as behavioral trials and in turn triggers the expression of the memory-related hippocampal neuronal sequence.

July 02, 2021 - 15:00

Daniel Aharoni
UCLA
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Developing new tools for imaging network dynamics in freely behaving animals

Abstract

One of the biggest challenges in neuroscience is to understand how neural circuits in the brain process, encode, store, and retrieve information. Meeting this challenge requires tools capable of recording and manipulating the activity of intact neural networks in freely behaving animals. Head-mounted miniature fluorescence microscopes are among the most promising of these tools. Taking advantage of the past decade of advancements in fluorescent neural activity reports, these microscopes use wide-field single photon excitation to image activity across large populations of neurons in freely behaving animals. They are capable of imaging the same neural population across months and in a wide range of different brain regions.

Initiated six years ago, the Miniscope Project -- an open-source collaborative effort-- aims at accelerating innovation of miniature microscope technology while also extending access to this technology to the entire neuroscience community. Currently, we are working on advancements ranging from optogenetic stimulation and wire-free operation to simultaneous optical and electrophysiology recording. Through continued optimization and innovation, miniature microscopes will likely play a critical role in extending the reach of neuroscience research and creating new avenues of scientific inquiry.

July 09, 2021 - 15:00

Seychelle M. Vos
MIT
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Pause & Go: Defining Promoter-Proximal Regulation of mammalian RNA Polymerase II

Abstract

RNA polymerase (Pol) II is regulated during all stages of transcription to ensure appropriate gene expression. In metazoans, Pol II frequently pauses in the region proximal to the promoter through its association with two protein complexes, DRB-sensitivity inducing factor (DSIF) and negative elongation factor (NELF). Release from pausing into active elongation is mediated by the kinase, P-TEFb.

To understand how pausing and pause release are regulated, we reconstituted mammalian paused and activated Pol II complexes and resolved their structures by cryo-EM. The structures along with biochemical assays show how NELF enhances Pol II pausing and how elongation factors compete with NELF to promote active elongation. Finally, we have recently determined how Pol II is stimulated to transcribe rapidly using an allosteric interaction with the elongation factor RTF1.

Together, our results provide the foundation for understanding the molecular basis of promoter proximal gene regulation and transcription through chromatin.

August 20, 2021 - 15:00

Alba Alfonso Garcia
UC Davis
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TBA

Abstract

TBA

September 03, 2021 - 15:00

Kanaka Rajan
Mount Sinai
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TBA

Abstract

TBA

October 01, 2021 - 15:00

Kerstin Bartscherer
Hubrecht Institute
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Tissue regeneration in the African spiny mouse

Abstract

Why tissue regeneration occurs in some animals but not in others remains enigmatic, and it is not clear why even some closely related species have different responses to the same type of injury.

Using naturally regenerating African spiny mice in comparative RNA-seq based approaches with poorly regenerating mammals, we investigate the molecular mechanisms that promote regeneration in different spiny mouse organs.

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Date Speaker Title and description
June 11, 2021 - 15:00

William Allen
Harvard University
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Mapping the neural basis of thirst motivation

Abstract

Understanding the neuronal basis of need-based motivational drives, such as thirst and hunger, has been a major goal in neuroscience and psychology for over a century. These drives, which maintain homeostasis by directing an animal’s behavior to satisfy specific physiological needs important for survival, are fundamental regulators of behavior. However, it has remained unclear how the activity of neurons sensing physiological state cause an animal to engage in specific motivated behaviors (e.g., eating or drinking) to maintain homeostasis.

I studied the motivational mechanisms underlying thirst, a drive vital for survival that is easily and rapidly induced in mice. Using a new transgenic mouse line that enabled Cre recombination in activity-defined populations of neurons, I was able to obtain highly specific and efficient genetic access to hypothalamic neurons that are activated upon water deprivation, and which integrate signals from cells that directly sense the animal’s physiological need for water. Through a series of molecular profiling, optogenetic, and activity recording experiments, I found that these thirst neurons form a specific cell type and encode a neural regulator of thirst that acts through aversive reinforcement.

It remained unclear how this small population of genetically-defined thirst neurons could shape the animal’s overall behavior. To answer this question, I developed a new approach using large-scale extracellular electrophysiology to map the flow of activity through an unprecedented ~24,000 single neurons in 34 regions of the mouse brain during thirst-motivated behavior. These experiments revealed both widespread neural correlates of sensory input and behavioral output and, surprisingly, a brain-wide neural activity state encoding thirst that could be causally induced through optogenetic stimulation of hypothalamic thirst neurons. These results are significant both in revealing the basic mechanisms of thirst, and in suggesting a new way to study the neural basis of behavior at the level of brain-wide activity patterns.

June 4, 2021 - 15:00

Sebastian Preissl
UC San Diego School of Medicine
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Uncovering cell type-specific gene regulatory programs and interpreting disease risk association using single-cell epigenomics

Abstract

Transcriptional regulatory regions in the genome including promoters and distal acting enhancers play fundamental roles for development and disease.

Genetic variants associated with human phenotypic traits and disease risk are enriched within cis-regulatory elements (CREs).

However, heterogeneity of primary tissues poses a significant challenge in mapping the precise chromatin landscape in specific cell types.

Therefore, we optimized single cell ATAC-seq protocols using droplet based and combinatorial barcoding based strategies for use on more than 25 flash frozen primary human and mouse tissue types including brain and heart.

Misregulation of gene expression in human hearts can result in cardiovascular diseases that are leading causes of morbidity and mortality worldwide. The limited information on the genomic location of candidate cis-regulatory elements (cCREs) in distinct cardiac cell types has restricted our molecular understanding of these diseases.

Using single nucleus ATAC-seq, we defined >287,000 cCREs in the four chambers of the human heart at single-cell resolution, which revealed cCREs and candidate transcription factors associated with cardiac cell types in a region-dependent manner and during heart failure.

We further discovered cardiovascular disease-associated genetic variants enriched within these cCREs including candidate causal atrial fibrillation variants localized to cardiomyocyte cCREs.

Two such risk variants residing within a cardiomyocyte-specific cCRE at the KCNH2/HERG locus resulted in reduced enhancer activity compared to the non-risk allele.

Finally, we found that deletion of the cCRE containing these variants decreased KCNH2 expression and prolonged action potential repolarization in an enhancer dosage-dependent manner.

Overall, this comprehensive atlas of human cardiac cCREs provides the foundation for illuminating cell type specific gene regulation in human hearts during health and disease.

May 28, 2021 - 15:00

Hiroki Asari
EMBL Rome
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"Inefficient" coding in the mouse retina

Abstract

Animals encounter different types of sensory signals depending on their natural habitats and lifestyles.

This can serve as an evolutionary driving force for each species to optimize its sensory systems for processing those signals that appear more frequently and are relevant for survival.

The optimality of the sensory processing has been broadly supported from a viewpoint of coding efficiency; however, here I would like to present and discuss two pieces of evidence that are inconsistent with what the efficient coding hypothesis implies on the mouse retina.

First, extracellular recordings from the optic tract of awake mice show that the retinal physiology in vivo violates the energy minimization principle.

Second, the analysis of the natural image statistics indicates that the functional dorsoventral division of the mouse retina is not optimal for efficiently encoding natural scenes in the UV-green spectra.

These data thus suggest that the mouse retina should have evolved under selective pressures beyond the coding efficiency, such as visual ethological demands.

May 21, 2021 - 15:00

Nicoletta Petridou
EMBL
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The onset of vertebrate gastrulation at a critical point of a tissue rigidity phase transition

Abstract

Embryo morphogenesis is impacted by dynamic changes in tissue material properties, which have been proposed to occur via processes akin to phase transitions (PTs).

Here, I will present how rigidity percolation provides a simple and robust theoretical framework to predict material/structural PTs of embryonic tissues from local cell connectivity.

By using percolation theory, combined with directly monitoring dynamic changes in tissue rheology and cell contact mechanics, we demonstrate that the zebrafish blastoderm at the onset of gastrulation undergoes a genuine rigidity PT, brought about by a small reduction in adhesion-dependent cell connectivity below a critical value.

We quantitatively predict and experimentally verify hallmarks of PTs, including power-law exponents and associated discontinuities of macroscopic observables.

We further explore the cellular mechanisms controlling the precision of this PT showing that it depends on blastoderm cells undergoing meta-synchronous divisions causing random and, consequently, uniform changes in cell connectivity.

Finally, our more recent results suggest that the early germ layers in zebrafish occupy different rigidity regimes of the rigidity percolation phase space which may be important in their early segregation at the onset of gastrulation.

May 7, 2021 - 15:00

Helen Baron
University of Oxford
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Neuronal computation underlying inferential reasoning in humans and mice

Abstract

Every day we make decisions critical for adaptation and survival.

We repeat actions with known consequences. But we also draw on loosely related events, to infer and imagine the outcome of entirely novel choices.

These inferential decisions are thought to engage a number of brain regions, however the underlying neuronal computation remains unknown.

In this talk I will show how a cross-species approach in humans and mice can be used to reveal the functional anatomy and neuronal computation underlying inferential decisions. I will show that during successful inference, the mammalian brain uses a hippocampal prospective code to forecast temporally-structured learned associations.

Moreover, during resting behaviour, short-timescale coactivation of hippocampal cells represent inferred relationships in sharp-wave/ripples, thereby “joining-the-dots” between events that have not been observed together but lead to profitable outcomes.

Computing mnemonic links in this manner may provide a general mechanism to build a cognitive map that stretches beyond direct experience, thus supporting flexible behavior.

April 30, 2021 - 15:00

Sebastian Eustermann
EMBL
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ATP-dependent chromatin remodelers: molecular stir bars or information processing hubs?

Abstract

ATP-dependent chromatin remodelers are macromolecular machines that govern the arrangement and composition of nucleosomes across eukaryotic genomes.

Understanding the mechanisms of these enigmatic enzymes promises to reveal core principles of genome regulation and maintenance.

However, the complexity of remodelers and their chromosomal substrates poses a major challenge for modern structural biology.

In my talk, I will discuss the recent breakthroughs which provided high-resolution cryoEM insights into all four families of remodelers.

I will highlight the emerging structural and mechanistic principles with a particular focus on multi-subunit SWI/SNF and INO80/SWR1 complexes.

A conserved architecture comprising a motor, rotor, stator and grip suggests a unifying mechanism how stepwise DNA translocation enables large scale reconfigurations of nucleosomes.

A molecular circuitry involving the nuclear actin containing module establishes a framework for understanding allosteric regulation.

By using whole genome chromatin reconstitutions, we probed these insights in a biochemically defined yet genome wide manner.

We identified DNA shape/mechanics motifs, distinct from known DNA sequence preference of histones, as sufficient information for nucleosome positioning.

Our findings establish a molecular mechanism for robust and yet adjustable +1 nucleosome positioning adjacent to gene promoter regions and, more generally, remodelers as information processing hubs that enable active organization and allosteric regulation of the first level of chromatin.

April 23, 2021 - 15:00

Vikas Trivedi
EMBL
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Axial organization in animal development: a synthetic approach

Abstract

Emergence of multicellular forms (tissues, organs and organisms) from cells through changes in their shape, size, number and organization is central to understanding the process of morphogenesis.

While molecular players are known, we do not know how the activity of genes and proteins is translated into 3D structures in space and time.

Preexisting spatial cues, species-specific geometry and extraembryonic signaling centers, confound studying these processes in vivo.

We have recently shown that 3D cell aggregates from different species (mouse embryonic stem cells and zebrafish blastula cells, which we term gastruloids and pescoids respectively) generate spatial asymmetries in gene expression and cell behavior within otherwise equivalent groups of cells, to develop a global coordinate system (body axes) de novo.

Combining light-sheet imaging with genetic labelling of cells we are now gaining some insights into the spatio-temporal precision and species-independent manner, with which such 3D embryonic cell aggregates generate the major body axes even in the absence of any embryonic information.

Using these embryonic organoids, as a minimal alternate system, sufficient to generate embryonic axes, we aim to understand early development in embryos as an emergent phenomenon of the self-organization of pluripotent cells.

April 16, 2021 - 15:00

Christina Kim
Stanford University
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Molecular circuits for recording intracellular signaling in neural ensembles

Abstract

Probing the molecular and functional properties of neural ensembles is essential for understanding how these networks give rise to circuit function and animal behavior.

I specialize in using molecular and optical approaches to study different types of neuronal signaling in the brains of awake behaving mice.

During my Ph.D. with Professor Karl Deisseroth, I studied the diverse firing properties of projection-defined prefrontal cortex neurons using real-time, cellular-resolution imaging techniques for recording activity from sparse projection pathways.

To allow investigations into the molecular cell-types of these activity- and projection-defined neurons, during my postdoctoral work with Professor Alice Ting I further developed and applied technologies inspired by synthetic biology to gain genetic access to activated cell ensembles.

I coupled single-cell RNA sequencing with a light- and calcium-dependent transcription reporter, FLiCRE, to map out a specific functional and molecular pathway in the brain.

This circuit could be genetically accessed and stimulated using FLiCRE to demonstrate that these neurons drive aversive behaviors in mice.

Together, these emerging technologies have revealed highly-resolved cortical cell-types defined by their transcriptome, projection targets, and activity patterns during behavior.

Future application of FLiCRE along with further development of new technologies will pinpoint the molecular mechanisms by which diverse neural pathways regulate downstream circuits and behavior.

April 9, 2021 - 15:00

Idse Heemskerk
University of Michigan
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Signaling, cell fate, and self-organized patterning.

Abstract

Human pluripotent stem cells can reproducibly organize into embryo-like and organ-like structures.

Efforts to produce pure cell populations for applications such as regenerative medicine are hampered by variability and heterogeneous cell fate outcomes.

In both cases the same biology is at play: developmental gene circuits give rise to endogenous signaling patterns in space and time that in turn give rise to cell fate patterns.

How cells establish these endogenous signaling patterns, and how those signals are then interpreted to give rise to different cell fates is poorly understood.

Recent work has shown that signaling patterns are not static and that cells may respond to different features of the dynamic signaling history such as the rate of signal change, raising the question of how the high dimensional space of possible signaling histories maps to the space of cell fates.

I will report on our ongoing work to answer these questions, which focuses on the cell fate decisions associated with gastrulation and early post-gastrulation development.

March 26, 2021 - 15:00

Sami El-Boustani
University of Geneva
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Sensorimotor representation in mice performing a whisker-based discrimination task

Abstract

Perceptual decision-making is characterized by widespread patterns of activity in the brain. Yet our understanding of the neuronal pathways that support these processes remains very limited.

We studied thalamocortical and cortico-cortical circuits involved in goal-directed sensorimotor transformations in mice performing a whisker-based discrimination task to understand how tactile sensations can be used to drive decisions. As mice learn to perform this task, on one end of the nervous system, tactile stimuli are encoded in the somatosensory pathways while on the other end, motor commands are issued reflecting decisions made.

Subdivisions of the whisker somatosensory thalamus project to cortex in a region-specific and layer-specific manner. A clear anatomical dissection of these pathways and their functional properties during whisker sensation is lacking. Here, we revealed parallel non-overlapping thalamic pathways with distinct representations of tactile and decision-related information during goal-directed sensorimotor task.

At the cortical level, wide field calcium imaging helped identified the secondary somatosensory cortex (wS2) and premotor cortex (M2) as part of the cortical network involved in sensorimotor transformation. Two-photon calcium imaging of large populations of neurons across layers of wS1, wS2 and M2 showed increase functional specialization along this pathway.

In particular, we found that projecting neurons in wS2 displayed decision-related responses suggesting that these neurons are important for the initiation of the upcoming movement generated in M2 cortical network. This was further corroborated with optogenetics manipulations of cortical activity during task execution.

Together these results highlight a shift in sensorimotor representations in the cortex underlying whisker-based goal-directed behavior.

March 19, 2021 - 15:00

Nacho Molina
IGBMC
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Uncovering gene regulation dynamics during the cell cycle in single embryonic stem cells

Abstract

Embryonic Stem cells (ESCs) show a robust yet plastic identity as they are capable of maintaining an efficient self-renewing state with a fast cell cycle while being responsive to external clues that lead to cell differentiation.

A core regulatory network formed by pluripotency transcription factors is responsible to maintain ESCs in this plastic pluripotent state. During mitosis chromatin is compacted, most transcription factors (TFs) are evicted from chromatin and transcription is globally downregulated.

To maintain PS cell identity, it is therefore required that transcription re-initiates at the appropriate set of genes after mitosis completion. Recently, it has been shown that some pluripotency TFs are able to bind to a subset of their target sites during mitosis.

This phenomenon, known as mitotic bookmarking, may represent a mechanism to maintain the memory of active transcription and therefore cell identity. Moreover, waves of intense transcription have recently been observed during mitotic exit and early interphase by using metabolic labeling of RNA in synchronized populations of HUH7 human hepatoma cells.

However, these studies did not consider that mitotic-arrested cell populations progressively de-synchronize and therefore the reported measurements are performed on mixture of cells at different internal cell-cycle times. Moreover, the treatment used for synchronization represents a considerable perturbation and therefore the gene expression dynamics in free cycling cells may differ substantially. Furthermore, it is still not fully understood the precise regulatory mechanism that drive gene expression dynamics during the cell cycle.

In my team, in particular, we try to address the following questions:

1) What is the precise gene expression dynamics during the cell cycle in ESCs?
2) How gene-specific mRNA synthesis and degradation rates change during the cell cycle?
3) What are the key transcriptional regulators that drive transcription dynamics during the cell cycle?

To address these questions, we have performed single-cell RNA sequencing of mouse ESCs and human fibroblast and infer the cell-cycle state progression of each cell applying advance machine learning methods; estimate transcription and degradation rates during the cell cycle using a biophysical model of gene regulation; and, identify key TFs underlying the transcriptional dynamics using linear regression models that relates gene expression with TF activity dynamics.

Overall, we believe that our results open the possibility to shed new light on the interplay between pluripotency maintenance, cell differentiation and the cell cycle.

March 12, 2021 - 15:00

Jakob Voigts
Janelia Research Campus
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Context-dependent sensory and spatial computations in mouse Retrosplenial Cortex

Abstract

Cognitive function requires holding multiple hypotheses in mind and interpreting sensory information differently depending on prior experience.

Here, we examined the cortical substrates of this process in a novel spatial inference task through modeling and electrophysiology in mouse Retrosplenial cortex (RSC).

We find evidence that spatial coding in RSC changes depending on previous landmarks the mouse has seen, which correlates with how much information the mouse has about its position.

We then examine whether this encoding of spatial information gained from previous sensory input could form the basis by which new sensory input is interpreted.

To build an interpretable model of this process, we trained a recurrent neural network on a simplified version of our task, and found that this network can correctly interpret otherwise ambiguous sensory information by exploiting local recurrent dynamics.

We then find that the activity dynamics in RSC fulfill the requirements for performing a similar computation.

In sum, we find that the population activity in RSC is capable of assigning different interpretations to otherwise ambiguous sensory inputs by encoding previous experience in a way where its attractor dynamics lead to different interpretations of identical subsequent sensory inputs.

March 5, 2021 - 15:00

Chii Jou (Joe) Chan
National University of Singapore
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Hydraulics, size control and tissue patterning in early mammalian development

Abstract

Many developmental processes involve the emergence of intercellular fluid and luminogenesis. This often results in a build up of hydrostatic pressure and signalling molecules in the lumen. However, the potential roles of lumina in cellular functions and tissue morphogenesis have yet to be fully explored.

Using mouse blastocyst as a model, we show that hydraulic force during lumen expansion leads to robust control of blastocyst size and cell fate specification1. We further showed that lineage segregation of the inner cell mass (ICM) can be guided by biochemical signalling cues from within the lumen2.

Notably, spatial segregation of the epiblast and primitive endoderm in the ICM is characterized by differential cellular dynamics and a fluid-solid transition in the overall ICM material property.

The interplay between hydraulics, signalling and tissue mechanics provides a unified framework in understanding tissue morphogenesis3, which we argue have important implications in understanding mammalian follicle development.

References

1. Chan CJ, Costanzo M, Ruiz-Herrero T, Mönke G, Petrie R, Bergert M, Diz-Munoz A, Mahadevan L, Hiiragi T. Hydraulic control of mammalian embryo size and cell fate. Nature (2019) 571:112-116.

2. Ryan AQ, Chan CJ, Graner F, Hiiragi T. Lumen expansion facilitates epiblast-primitive endoderm fate specification during mouse blastocyst formation. Developmental Cell (2019) 51, 1-14.

3. Chan CJ, Hiiragi T. Integration of luminal pressure and signalling in tissue self-organisation. Development (2020) 147:dev181297

Feb 26, 2021 - 15:00

Pim J. Huis in t Veld
Max Planck Institute for Molecular Physiology
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How do chromosomes attach to microtubules during cell division?
From piconewtons to phosphoregulation with biochemical reconstitutions.


Abstract

Accurate chromosome segregation in eukaryotes requires the coordinated action of hundreds of proteins. Subsets of these, named kinetochores, attach centromeric chromatin to the microtubules of the mitotic or meiotic spindle.

Kinetochores are crucial for accurate cell division: they couple the force of depolymerising microtubules to chromosome movement and delay the onset of anaphase until all chromosome-spindle attachments are correct.

The main microtubule binder in the kinetochore is Ndc80, a 65 nm long tether-like complex. In a human kinetochore, ~200 Ndc80 complexes connect a centromere to ~15 microtubules.

How does this lawn of Ndc80 bind dynamic microtubules and how is microtubule-attachment regulated during mitosis?

To address those questions, I reconstituted the kinetochore-microtubule attachment site from purified components and, together with colleagues, compared how the kinetochore-microtubule interface is regulated in a minimal in vitro system and in dividing cells.

Our work provides a quantitative description of microtubule binding under force and a molecular explanation for causes and consequences of Ndc80 multivalency.

Feb 19, 2021 - 15:00

Jesse Veenvliet
Max Planck Institute for Molecular Genetics
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Creating to understand: engineering the post-implantation mammalian embryo in a dish

Abstract

Post-implantation embryogenesis is a highly dynamic process comprising multiple lineage decisions and morphogenetic changes that are inaccessible to deep analysis in vivo.

The developmental engineering of embryo-like structures from stem cells in vitro can overcome this impediment.

Gastruloids are aggregates of mouse embryonic stem cells that resemble the organized gene expression space of the post-occipital embryo (i.e. an "embryo without a head"), but lack proper morphogenesis, e.g. presomitic mesoderm does not condense into somites and neural cells do not form a neural tube.

We recently discovered that the addition of the extracellular matrix surrogate Matrigel could transform the organized gene expression space of gastruloids into highly organized “trunk-like structures” (TLSs) with embryo-like architecture, comprising the neural tube and bilateral somites.

Comparative single-cell RNA sequencing analysis confirmed that this process is highly analogous to mouse development and follows the same stepwise gene-regulatory program.

Tbx6 knockout TLSs developed additional neural tubes mirroring the embryonic mutant phenotype, and chemical modulation could induce excess somite formation. TLSs thus reveal an advanced level of self-organization and provide a powerful platform for investigating post-implantation embryogenesis in a dish.

In my talk, I will give an overview of the development and benchmarking of the TLS system and discuss how it can be utilized to achieve quantitative biological insights.

Feb 12, 2021 - 15:00

Arseny Finkelstein
Janelia Research Campus
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Mechanisms of cortical communication during behavior

Abstract

Regulation of information flow in the brain is critical for many forms of behavior.

In the first part of my talk, I will focus on mechanisms that regulate interactions between brain regions and describe how information flow from the sensory cortex can be gated by state-dependent frontal cortex dynamics during decision-making in mice.

In the second part, I will focus on information flow within the frontal cortex microcircuitry and present a new optical method that I developed for rapid mapping of local connectivity in vivo.

Combining connectivity mapping with a novel paradigm of mouse innate behavior revealed a columnar structure in the frontal cortex and the existence of neurons that function as network hubs, which had an unexpectedly high number of connections and strong influence on neighboring neurons.

Finally, I will show that analyses of interactions between >20,000 neurons, recorded simultaneously across multiple cortical areasand different brain states, revealed a hitherto unknown parcellation of the mouse cortex into functional modules, calling for revision of existing definitions of cortical regions.

Taken together, these results pave a road to study how neuronal interactions on different spatial scales give rise to behavior.

Feb 5, 2021 - 15:00

Arnaud Krebs
EMBL
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Cooperativity and antagonism in transcription regulation

Abstract

Establishment of correct gene expression patterns is crucial for organism development and their perturbation is a key event in the manifestation of many diseases including cancer.

Binding of transcription factors (TFs) to cis-regulatory elements (CREs) opens chromatin and leads to the recruitment of multiple co-factors that activate or repress transcription.

CRE activation typically requires the binding of multiple TFs, however the precise mechanisms underlying their coordinated action are largely unknown. Current bulk assays used to map TF occupancy average binding events arising from millions of individual cells, not informing on the dependencies that organize their binding at CRE.

To move beyond this boundary, we have adapted Single Molecule Footprinting (SMF) to quantify the binding of TFs at mouse regulatory regions.

Detecting multiple TF binding events on single DNA molecules has enabled us to determine TF co-binding frequencies in vivo. Systematic analysis of the co-occupancy patterns of thousands of TF pairs reveals widespread evidence of cooperative binding independently of the identity of the factors involved.

We find that genomic distance between motifs, but not their strict spatial arrangement within CREs determines their degree of co-occupancy. Moreover, TF co-binding is prevalent at CREs with high nucleosome occupancy, suggesting that cooperative binding is required for maintaining chromatin open at regulatory regions.

These findings elucidate the binding cooperativity mechanism used by transcription factors in absence of strict organisation of their binding motifs, a characteristic feature of most of enhancers.

Jan 29, 2021 - 15:00

Bilal Bari
John Hopkins University
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Value representations in medial prefrontal cortex and ventral pallidum drive learning

Abstract

Natural environments are dynamic, necessitating rapid learning and flexible behavior to maximize reward. In the framework of reinforcement learning, memories of previous interactions with the environment form value representations - the basis for reward predictions.

We have explored the neural basis of these reward memories, how they are maintained, how they are updated, and how they drive behavior.

In one study, we trained mice on a dynamic foraging task in which they chose between alternatives that delivered reward with changing probabilities. Mice were sensitive to changes in reward contingencies and shifted behavior rapidly to maximize reward. We found that neurons in the medial prefrontal cortex, including projections to the dorsomedial striatum, persistently maintained memories of previous choices/outcomes and causally drove future decisions and the vigor of those actions.

In another study, we trained rats to associate cues with probabilistic delivery of rewards. We made the unexpected discovery that the ventral pallidum, a basal ganglia structure, encoded reward prediction errors, a necessary teaching signal to update reward memories. This activity bidirectionally modulated the vigor of reward-seeking behavior.

In contrast to a long-held view that ventral pallidum serves as a relay, these representations were much weaker in its primary input structure, the nucleus accumbens. Taken together, this work better defines the neural architecture of reinforcement learning.

*** Postponed ***
Jan 22, 2021 - 15:00

Kerstin Bartscherer
Hubrecht Institute
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Tissue regeneration in the African spiny mouse

Abstract

Why tissue regeneration occurs in some animals but not in others remains enigmatic, and it is not clear why even some closely related species have different responses to the same type of injury.

Using naturally regenerating African spiny mice in comparative RNA-seq based approaches with poorly regenerating mammals, we investigate the molecular mechanisms that promote regeneration in different spiny mouse organs.

Jan 15, 2021 - 15:00

Antonio Fernandez-Ruiz
Cornell University
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Cortico-hippocampal network dynamics for learning and memory

Abstract

Animals use memories of previous experiences to guide behavior in a flexible manner. The hippocampus and associated cortical structures play a key role in learning and memory processes. The synchronous spiking of cell ensembles in these circuits supports the encoding and recall of behaviorally relevant information, while neural oscillations coordinate inter-areal communication. In the first part of the talk, I will present novel evidence on the existence of dedicated entorhinal-hippocampal circuits and physiological mechanisms for different types of learning in rodents. The lateral (LEC) and medial (MEC) entorhinal cortex receive inputs from two distinct streams of cortical hierarchy (the ‘what’ and ‘where’ paths) and convey these neuronal messages to the hippocampus. I will show how this two inputs engage different hippocampal cellular populations in a task-dependent manner and how optogenetic manipulations that impair the precision timing of spikes affect learning performance and interareal communication. Hippocampal cells that have been active during a recent experience are reactivated during highly synchronous network events known as sharp-wave ripples (SWRs). This “replay” of behaviorally relevant sequences during SWRs after a new experience is believed to mediate memory maintenance and behavioral planning. In the second part of the talk, I will provide causal evidence on how the sequential activation of place cell ensembles during ‘offline’ periods contribute to memory.

Jan 8, 2021 - 15:00

Lucas Farnung
Harvard Medical School
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Machines on Genes
New Insights into Chromatin Transcription


Abstract


Transcription of eukaryotic protein-coding genes requires RNA polymerase II (Pol II).

During transcription, RNA polymerase II transcribes a chromatinized DNA template.

Pol II passage, however, is impaired by nucleosomes and requires elongation factors including chromatin remodellers and histone chaperones that facilitate chromatin transcription.

To understand the mechanistic basis of nucleosome passage, we have obtained multiple cryo-electron microscopy (cryo-EM) structures of transcribing RNA polymerase II from the yeast Saccharomyces cerevisiae engaged with a downstream nucleosome core particle and additional factors.

The structures and biochemical data provide a structural basis to investigate the interplay of Pol II, transcription factors, chromatin remodellers, histone chaperones, and nucleosomes.

Dec 18, 2020 - 15:00

Thibaut Brunet
UC Berkeley
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Choanoflagellates and the origin of animal morphogenesis

Abstract

Contractile cell types are universally present in animals and fundamental to animal morphogenesis and behavior.

Contractions of individual, scattered cells underlies amoeboid cell migration, which is prevalent in both adult organisms and embryos, while tissue-scale collective cell contractility underlies both embryonic morphogenesis and adult motricity.

However, the origin of animal contractile cell types remains obscure. As the sister-group of animals, choanoflagellates hold the promise of illuminating the evolutionary origins of animal cell biology.

Intriguingly, choanoflagellate genomes encode an extensive complement of homologs to animal contractility genes, suggesting the involvement of (yet unidentified) contractile processes in their life history.

Here, I report on the recent discovery of both individual and collective cell contractility in choanoflagellates.

Under confinement, the model choanoflagellate Salpingoeca rosetta rapidly undergoes a phenotypic switch from a flagellate to an amoeboid cell phenotype that resemble animal migratory cells in both structure and function.

This represents an unexpected expansion of the known phenotypic repertoire of choanoflagellates and suggests an ancient origin for animal crawling cells, in line with the temporal-to-spatial transition hypothesis for the origin of animal cell types.

Finally, collective cell contractility has also been recently discovered in a newly discovered colonial choanoflagellate isolated from a Carribean island, that undergoes rapid and reversible whole-colony inversion in response to external photic and mechanical stimuli.

Dec 11, 2020 - 15:00

Aurele Piazza
ENS Lyon
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Cohesin-mediated chromatin folding regulates homology search during recombinational DNA repair

Abstract

Homologous recombination(HR) is a ubiquitous DNA double-strand break (DSB) repair mechanism that promotes cell survival and genomic stability.

HR entails a potentially genome-wide homology search step, carried out along a conserved RecA/Rad51-ssDNA nucleoprotein filament (NPF) assembledon each DSB ends 1–3.

This search is subdued to the NPF-dsDNA collision probability with any given loci. However, whether chromatin spatially reorganizes following a DSB, and how it in turn influences the homology search process, remains undefined.

Here we characterize the local and genome-wide spatial reorganization of chromatin following DSB formation, and show that they influence homology search in multiple ways.

Cohesin folds chromosomes into cohesive arrays of ~20 kb long chromatin loops as cells arrest in G2/M.

Locally, the DSB-flanking regions interact in a resection- and 9-1-1 clamp-dependent manner, independently of cohesin and HR proteins.

This local structure blocks cohesin progression, constraining the extending NPF at loop base and promoting side-specific NPF-dsDNA interactions.

Functionally, cohesin-mediated loop folding (but not sister chromatid cohesion) restrains homology search intra-chromosomally, which provides a kinetic advantage for identification of intra- over inter-chromosomal homology.

Together with pastin vitrodata, our results suggest that cohesins act as general facilitators of homology search, by promoting both 1D scanning upon loop expansion and localized 3D inter-segmental contact sampling upon global reorganization of chromatin conformation.

Dec 4, 2020 - 15:00

Ann Kennedy
Northwestern University
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Hypothalamic representations of internal state and behavior

Abstract

In order to survive and reproduce, animals must produce a diverse range of innate and learned behaviors in a flexible and context-dependent manner.

The computational task of forming an internal representation of an animal’s environment and translating that to the selection of goal-directed actions is dependent on the coordinated activity of multiple brain areas.

Working with experimentalists to dissect the neural correlates of behavior in multiple interconnected hypothalamic nuclei of freely behaving mice, we uncover striking differences in how animals’ motivational states and behaviors are represented across neural populations.

Combined with neuronal cell type data, these observations inform a new model of the joint control of behavioral decision-making by multiple interacting neuronal populations.

Nov 27, 2020 - 15:00

Yohei Yamauchi
University of Bristol
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Neuropilin-1 promotes SARS-CoV-2 entry and spread by binding the furin processed SARS-CoV-2 Spike and is a target for antiviral intervention.

Abstract

SARS-CoV-2 is the coronavirus responsible for the current COVID-19 pandemic.

Normal human coronaviruses cause the common seasonal cold that cause mild respiratory symptoms.

Why SARS-CoV-2 is capable of spreading so effectively among humans, why it infects organs other than the lung, why it causes neurological symptoms such as loss of taste and smell, is not clear.

The SARS-CoV-2 Spike (S) is a viral surface protein that binds the receptor ACE2 and is essential for host cell attachment and entry.

We noticed that furin protease cleavage of S at the S1/S2 boundary liberates a sequence that conforms to the C-end Rule [R/K]-X-X-[R/K] at the S1 C-terminus.

We found that this C-end Rule binds directly to the cell surface receptor neuropilin-1 (NRP1) - in non-infected cells, NRP1 has roles in ligand internalisation, angiogenesis and regulation of vascular leakage. We further showed that depletion of NRP1 by CRISPR/Cas9, blockade of the S1-NRP1 interaction with NRP1 antagonist or anti-NRP1 mAbs significantly reduced SARS-CoV-2 infectivity in human tissue culture cells.

Thus, NRP1 is a second receptor for SARS-CoV-2 that promotes viral infectivity, and is a target for therapeutic intervention of COVID-19.