Best Poster Awards – The Identity and Evolution of Cell Types

The second edition of the EMBO | EMBL Symposium: The Identity and Evolution of Cell Types brought together an increased number of researchers from this growing community. 315 scientists joined the virtual meeting and enjoyed four days of talks and poster presentations streamed live. A total of 72 posters were presented at the two live poster sessions out of which three were selected as the best posters by popular vote. Take a look at the winners and their work.

Molecular fingerprinting sea anemones and jellyfish: A transcriptomic approach to characterize Cnidarian cell types
image of Alison Cole
Alison Cole, University of Vienna, Austria

Presenter: Alison Cole, University of Vienna, Austria

Abstract

Animals typically consist of hundreds of different cell types, yet the evolutionary mechanisms underlying the emergence of new cell types are unclear. Cnidarians offer advantages to studies of metazoan cell type evolution, as they are the sister group to the Bilateria and yet comprise an extremely diverse set of lineages that exhibit variable life history strategies, life spans, regenerative properties, animal-defining cell types (ie. muscles and neurons), as well as clade-specific cell types (i.e. cnidocytes). Advances in single cell RNA sequencing have opened the frontiers for molecular profiling of cell types at a genome-wide scale. Application of these technologies for comparisons across species remains in its infancy, and is largely, but not exclusively, restricted to closely related species with well-defined orthologous gene sets. Here we present a large single cell dataset derived from the anthozoan polyp Nematostella vectensis (comprising both developmental and tissue-derived samples),the scyphozoan moon jelly (Aurelia aurita; comprising all life history stages as well as medusa tissue-derived samples), and the hydrozoan Clytia hemispherica (young medusa only). The same cell complement that is identifiable from species-specific genome-wide analyses is recoverable using only a set of 1:1:1 orthologous genes in all three species. Analyses of the reduced gene matrix combining all three species robustly identifies putatively homologous cell types amongst the neurosecretory derivatives, as well as cell populations with clear species-specific transcriptomic profiles. Interpretations of these data in the light of specific cell types will be discussedin order to demonstrate that the combination of unbiased single cell transcriptomes and gene-directed validations can permit the identification of novel and conserved cell types.

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Stylophora pistillata cell atlas illuminates stony coral symbiosis, calcification and immunity
Anamaria Elek, Centre for Genomic Regulation, Spain

Presenter: Anamaria Elek, Centre for Genomic Regulation, Spain

Abstract

Stony corals are colonial cnidarians that sustain the most biodiverse marine ecosystems on Earth: coral reefs. Life cycle of these animals involves a swimming larva that settles and metamorphoses into a sessile polyp, which in turn develops into the adult stage, depositing in the process a protein rich organic matrix and extracellular calcium carbonate crystals to form a stony skeleton. Despite their ecological importance, little is known about the cell types and molecular pathways that underpin the biology of reef-building corals. Using single-cell RNA sequencing, we have defined over 40 cell types across the three life stages of a stony coral Stylophora pistillata. Among others, we characterized previously unknown coral immune cells, endosymbiont alga-hosting cells, and calicoblasts responsible for calcium-carbonate skeleton formation in both settling polyp and the adult coral. Apart from these specialized coral cell types, we identified evolutionary conserved cell types by phylogenetic integration of our S. pistillata cell atlas with three other available cnidarian species. These evolutionary conservations include neuronal and gland cell types, cnidaria-specific cnidocytes, and others. Overall, this study reveals the molecular and cellular basis of stony coral biology, and addresses the evolution of cell type programs in three major cnidarian lineages separated by 500 million years of evolution.

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Gene family evolution underlies cell type diversification in the hypothalamus of teleosts*
Maxwell Shafer, Biozentrum, University of Basel, Switzerland

Presenter: Maxwell ShaferBiozentrum, University of Basel, Switzerland

Abstract

Hundreds of cell types form the vertebrate brain, but it is largely unknown how similar these cellular repertoires are between or within species, or how cell type diversity evolves. To examine cell type diversity across and within species, we performed single-cell RNA sequencing of ~130,000 hypothalamic cells from zebrafish (Danio rerio) and surface- and cave-morphs of Mexican tetra (Astyanax mexicanus). We found that over 75% of cell types were shared between zebrafish and Mexican tetra, which last shared a common ancestor over 150 million years ago. Orthologous cell types displayed differential paralogue expression that was generated by sub-functionalization after genome duplication. Expression of terminal effector genes, such as neuropeptides, was more conserved than the expression of their associated transcriptional regulators. Species-specific cell types were enriched for the expression of species-specific genes, and characterized by the neo-functionalization of members of recently expanded or contracted gene families. Within species comparisons revealed differences in immune repertoires and transcriptional changes in neuropeptidergic cell types associated with genomic differences between surface- and cave-morphs. The single-cell atlases presented here are a powerful resource to explore hypothalamic cell types, and reveal how gene family evolution and the neo- and sub-functionalization of paralogs contribute to cellular diversity.

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*https://doi.org/10.1101/2020.12.13.414557 


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Best Poster Awards: Friend or Foe — Transcription and RNA Meet DNA Replication and Repair

During the second virtual EMBO | EMBL Symposium of the year three scientists were awarded a prize for their scientific poster. In this blog, we present the winners and their research.

Friend or Foe attracted 336 participants worldwide, discussing transcription and RNA and DNA replication and repair in live sessions and panel discussions. Three poster session rounds gave the opportunity for participants to view 72 digital posters and interact with the poster presenters.

After the sessions, a voting round followed and three presenters were distinguished with a best poster award by popular vote.

  1. Gianluca Sigismondo of the German Cancer Research Center in Heidelberg, Germany.
  2. Tycho Mevissen, Howard Hughes Medical Institute and Harvard Medical School, USA
  3. Sara Luzzi, Newcastle University, UK

Read our blog on how to create a prize-winning digital poster.

Chromatin dynamics during DNA repair investigated via chromatin-directed proteomics

A portrait picture of scientist Gianluca Sigismondo
Gianluca Sigismondo, German Cancer Research Center, Germany. PHOTO: Gianluca Sigismondo

Poster presenter: Gianluca Sigismondo

Authors: Gianluca Sigismondo, Lavinia Arseni, Jeroen Krijgsveld

DNA lesions predispose to genomic instability, a hallmark of cancer; therefore cells have evolved repair pathways to solve those harmful insults.

Double-strand breaks (DSBs) represent the most lethal DNA damage first marked by the phosphorylation of the histone H2A.X (γH2A.X) which triggers the recruitment of sensor proteins belonging to either the error-prone non-homologous end joining (NHEJ) or the efficient homologous recombination (HR) pathway.

It is now established that chromatin has an active role also in DNA repair, thus its characterization at DSB repair foci is essential to better understand the coordinate action of the repair mechanisms and to identify novel players participating in tumor-associated apoptotic resistance and cell survival.

Here we dissect chromatin changes upon exposure to ionizing radiations through multiple proteomics-based approaches. We applied the Selective Isolation of Chromatin-Associated Protein strategy (ChIP-SICAP; Rafiee, 2016) to investigate the interactors of core NHEJ, HR proteins and γH2A.X while bound to the DNA or in the chromatin soluble fraction.

Through a click chemistry-assisted procedure we profiled the configuration of DNA-bound proteins during DSBs repair; finally we analyzed the histone post-translational modifications (hPTMs) cross-talk at mono-nucleosomes marked by γH2A.X.

Our integrated analysis identified the dynamics of expected chromatin determinants during the DNA repair and interestingly suggested the role for new candidates specifically enriched upon DSB formation.

Validation experiments based on monitoring of DSB foci formation and resolution in AID-DIvA cells proficient or knock-down cells provided evidence of a role for novel candidates in DNA repair. FACS-based analysis of Traffic-light Reporter (TLR) isogenic cells upon silencing of proteins identified by MS characterized their functional role in NHEJ, HR or pathway choice. Furthermore, we defined hPTMs associated with γH2A.X-marked mono-nucleosomes and their dynamics during DSB resolution.

This analysis corroborated expected enrichments (e.g. H4K20me1/me2) and provided insights on new modifications specifically enriched at γH2A.X-nucleosomes.

Chromatin dynamics during DNA repair investigated via chromatin-directed proteomics

Towards transcription-coupled DNA repair in Xenopus egg extract

Poster presenter: Tycho Mevissen

A portrait of scientist Tycho Mevissen
Tycho Mevissen, Harvard Medical School, USA. PHOTO: Tycho Mevissen

This poster and abstract contain unpublished data and are not available at this moment.

Tycho Mevissen is a postdoctoral research fellow in Johannes Walter’s lab at Harvard Medical School. He had completed his PhD with David Komander at the MRC Laboratory of Molecular Biology in Cambridge, UK, where he used structural and biochemical tools to elucidate the intricate mechanisms of enzymes in the ubiquitin system, in particular deubiquitinases (DUBs).

His current research interests in the Walter lab revolve around molecular mechanisms at the intersection of DNA transcription, replication and repair.

In particular, he is interested in understanding how elongating RNA polymerase II deals with various types of obstacles – including different DNA lesions – during transcription elongation. To study this, he uses Xenopus egg extract, which is a powerful cell-free system that has been successfully used to recapitulate a wide range of cellular DNA repair pathways.


RBMX enables productive RNA processing of ultra long exons important for genome stability

A portrait picture of scientist Sara Luzzi
Sara Luzzi, Newcastle University, UK. PHOTO: Sara Luzzi

Poster presenter: Sara Luzzi

Authors: Sara Luzzi, Gerald Hysenaj, Chileleko Siachisumo, Kathleen Cheung, Matthew Gazzara, Katherine James, Caroline Dalgliesh, Mahsa Kheirollahi Chadegani, Ingrid Ehrmann, Graham R Smith, Simon J Cockell, Jennifer Munkley, Yoseph Barash, and David J Elliott.

The nuclear RNA binding protein RBMX has a direct role in genome repair and is required for expression of the tumour suppressor BRCA2. Here we report that RBMX controls RNA processing of key genes involved in genome maintenance in breast cancer cells.

Our data demonstrate that RBMX represses a premature polyadenylation site that would truncate BRCA2 protein, and is essential for full-length mRNA expression from other genes important for genome stability. These include ETAA1, which encodes for a key replication fork protein, where RBMX and its protein interaction partner Tra2ß efficiently suppress a weak splice site to enable ETAA1 protein expression.

More generally, we propose that RBMX facilitates correct inclusion of unusually long exons within mature mRNAs by repressing cryptic RNA processing. Our data provide new molecular insights explaining the role of RBMX in DNA repair and genome maintenance.

Poster RBMX enables productive RNA processing of ultra-long exons important for genome stability

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Best Poster Awards – In Situ Structural Biology Workshop

The EMBO Workshop: In Situ Structural Biology: From Cryo-EM to Integrative Modelling was our final virtual conference of 2020, but there was no trace of Zoom fatigue amongst the 466 participants who joined us from 6 – 8 December!

80 international researchers presented their posters during the two posters sessions on the following topics:

  • Biophysical analysis in cells
  • COVID-19
  • Imaging across scales
  • Integrative modelling
  • Molecular sociology
  • Structural analysis in situ
  • Structural biology

Each of the participants had the chance to vote for their favourite poster, resulting in two posters winning the Best Poster Award kindly sponsored by EMBO Press.  Here are the winners:

New insights on the catalytic mechanism of arsenite oxidase

PHOTO: Filipa Engrola

Authors: Filipa Engrola, Márcia Correia, Teresa Santos-Silva, Maria Romao, (UCIBIO@FCT-NOVA, Portugal)

Arsenic (As) and antimony (Sb) are two metalloids that, due to anthropogenic and natural causes, pose an environmental  threat, considered as priority pollutants by the World Health Organisation and the United States Environmental Protection Agency. Although the safety guards recommend a maximum of 10 μg/L of As and Sb in drinking water, these values are exceeded in many regions worldwide, with no remediation approach that is simultaneously effective, clean and economically sustainable [1,2]. The ancient bioenergetic enzyme arsenite oxidase (Aio), from microorganisms Rhizobium sp. NT-26 (NT-26 Aio) and Alcaligenes faecalis (A.f. Aio), is currently being studied for its use as a biosensor and in bioremediation processes. Both Aio enzymes contain a large subunit (AioA) that harbours a molybdenum centre and a [3Fe-4S] cluster, and a small subunit (AioB) that possess a Rieske [2Fe-2S] cluster and have demonstrated to oxidise AsIII, as well as SbIII, into the easier to remove and less toxic forms of AsV and SbV, respectively [3,4]. Aiming to elucidate the catalysis mechanism of the enzymes, a combination of expression and purification of the proteins, crystallisation, structural analysis, enzyme kinetics and affinity tests were conducted. X-ray structures of the ligand-free form of the enzyme had been previously determined (PDB: 4AAY, 5NQD and 1G8K [3,5,6]). In our work, Aio crystals in complex with two different forms of the substrate analogue – Sb oxyanions, with a reaction kinetic 6500 times slower than AsIII [6] – diffracted up to ca 1.8 Å resolution. The structures show the reaction intermediates bound at the active site, with a μ-oxo bridge binding Sb to the Mo atom. Analysis of bond lengths and geometry of the ligands at the Mo active site allowed us to revisit the catalytic mechanism of As oxidation [7], contributing to the understanding and future biotechnological application of this family of enzymes in water treatment.

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Allosteric hotspot in the main protease of SARS-CoV-2

PHOTO: Léonie Ströhmich

Authors: Léonie Strömich, Sophia N Yaliraki, (Imperial College London, UK)

Since the beginning of 2020 we have seen the coronavirus SARS-CoV-2 causing a global pandemic with almost 34 million cases and over 1 million deaths worldwide [as of 01.10.2020] [1.] As a result, we have seen a surge in research efforts to develop effective treatments for the underlying disease, COVID-19. One approach is to target the main protease (Mpro) of SARS-CoV-2 as it is essential for virus replication in an early step of the viral life cycle [2.] Most efforts are centred on inhibiting the orthosteric binding site of the enzyme. However, considering allosteric sites on the protein allows for more selective drug design and widens the chemical search space. Here, we report an allosteric hotspot in the SARS-CoV-2 Mpro dimer by using novel atomistic graph theoretical methods: Markov transient analyses follow the propagation of a random walker on a graph and have been shown to successfully identify allosteric communication in catalytic proteins [3.] We further score the so identified allosteric hotspots against random sites in similar distances and thus identify a statistically significant putative allosteric site in the SARS-CoV-2 Mpro. We then simulate a binding event at this hotspot region using data from a recent XChem fragment screen by the Diamond Light Source [4.] which provides a starting point for rational drug design. This study uses highly efficient network theoretical models to shed light on allosteric communication and uncovers putative allosteric sites in the SARS-CoV-2 main protease. This provides a valuable contribution to the ongoing efforts to find a cure against COVID-19 by broadening the horizon for drug discovery efforts.

Image: Léonie Ströhmich

References:
[1.] Official World Health Organization COVID-19
dashboard: https://covid19.who.int (Accessed: 01.10.2020).
[2.] Hilgenfeld, R. (2014). FEBS Journal, 281(18), 4085-4096.
[3.] Amor, B., Yaliraki, S. N., Woscholski, R., & Barahona, M. (2014) Molecular BioSystems, 10(8), 2247-2258.
[4.] Douangamath, A., Fearon, D., Gehrtz, P., Krojer, T., Lukacik, P., Owen, C. D., … Walsh, M. A. (2020) Nature Communications, 11, 5047.

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Expanding the Druggable Proteome with Chemical Biology – Best Poster Awards

The 2020 conference season at the EMBL Advanced Training Centre kicked off with the EMBL Conference: Expanding the Druggable Proteome with Chemical Biology (5 – 7 February 2020). Meet the three poster prize winners from the conference – Patrick Zanon, Enric Ros and Rens de Vries.

Identification of novel antibiotic targets using covalent inhibitors and residue-specific proteomics

PHOTO: Patrick Zanon

Authors: Patrick Zanon (1), Stephan Hacker (1)

Bacterial resistance towards all marketed antibiotics poses an imminent threat to global health. In order to overcome this antibiotic crisis, drugs with novel mechanisms-of-action are desperately needed. Covalent inhibitors are especially promising in this regard as they are already prevalent as antibiotics (e.g. β-lactams and fosfomycin), allow targeting protein pockets that are hard to address with non-covalent interactions alone and hold the promise to overcome some mechanisms of resistance development.[1] Furthermore, covalent inhibitors are uniquely suited to identify new binding pockets on proteins using residue-specific proteomics and in this way to broaden the scope of targetable protein targets.
The vast majority of covalent inhibitors so far either hijack the enzymatic activity of the protein by modification of catalytic serines and tyrosines or address cysteines through their inherent outstanding nucleophilicity. Nevertheless, the number of potentially addressable proteins in the bacterial proteome is significantly limited by the requirement for these amino acids to be present in target proteins. By developing electrophilic groups that are selective for other amino acids (e.g. lysine), we strive to expand the number of exploitable interaction sites for covalent inhibitors in the bacterial proteome. Furthermore, to assess the reactivity and selectivity of covalent inhibitors and to streamline the discovery of novel antibiotic targets, we develop new methods for residue-specific activity-based protein profiling.[2,3] In this way, we are convinced, that we will be able to make important contributions to overcome the antibiotic crisis.

References:
[1] R. A. Bauer, Drug Discov. Today 2015, 20, 1061–1073.
[2] K. M. Backus et al., Nature 2016, 534, 570.
[3] P. R. A. Zanon, L. Lewald, S. M. Hacker Angew. Chem. Int. Ed., doi: 10.1002/anie.201912075.

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(1) Technical University of Munich, Germany


Incorporating 1,2,4,5-tetrazines into proteins: A method for targeted drug release

PHOTO: Enric Ros

Authors: Enric Ros (1), Antoni Riera (1), Lluís Ribas de Pouplana (1)

Bioorthogonal reactions, namely reactions that can take place under biocompatible conditions, are having a major impact in the development of new research tools and novel therapeutic strategies. In the latter case, the discovery of the reaction commonly referred to as “click-to-release” (CtR), which triggers the liberation of a given cargo (normally a drug or a fluorophore), has led to several applications in drug delivery. This reaction happens between a 1,2,4,5-Tetrazine (Tz) fragment and certain alkenes or alkynes and, in order to achieve drug delivery specifically at the site of action, one of the two reactant counterparts should be conjugated to a biomolecule acting as a carrier, ideally a protein.
We have synthetized the previously unreported 3-bromo-1,2,4,5-tetrazine and used its excellent reactivity to attain chemoselective protein labelling onto lysines. Due to the chemical features of the formed amino-Tz. The resulting labelled lysines can undergo fast CtR reactions with trans-cyclooctenes, thereby releasing a desired cargo under physiological conditions. To showcase the applicability of this approach, we have labelled the monoclonal antibody Trastuzumab (anti-Her2) and demonstrated the specific release of the cytotoxic drug doxorubicin upon reaction in a mammalian cell culture context, resulting in a decrease in cell viability.
Additionally, we have also used 3-bromo-1,2,4,5-tetrazine to synthetize an amino-Tz containing non-natural amino acid and used it to achieve protein labelling through its genetic incorporation by amber codon suppression in Escherichia coli. The resulting site-selectively labelled proteins can also trigger fast, high yielding CtR reactions.
To summarize, we have successfully applied a new compound, 3-bromo-1,2,4,5-tetrazine, as a reagent to achieve either chemoselective or site selective protein labelling. We have applied the bioconjugated proteins to demonstrate their potential use for targeted drug delivery in a relevant cellular model, opening new therapeutically useful methodologies.

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(1) IRB Barcelona, Spain


Modulation of nuclear receptors through ligand architecture

PHOTO: Rens de Vries

Authors: Rens de Vries (1), Femke Meijer (1), Luc Brunsveld (1)

Nuclear receptors (NRs) have been one of the primary drug targets over the last decades for their ability to regulate gene expression. The traditional approach of modulating NRs is to design small synthetic molecules that interact with the ligand-binding domain (LBD) of the NR. Ligands can thereby either enhance or inhibit gene transcription. Apart from the effects on transcription, recent research shows that minor changes in the ligand scaffold can have a significant impact on the behavior of the NR. In this research, we show how small-molecules can change both the dimerization behavior of NRs and the recruitment of allosteric modulators.
The Retinoic X Receptor α (RXRα) is known as a master regulator among NRs through its ability to heterodimerize with, and thereby modulate, other NRs. We show, using a novel NanoBIT complexation assay, that small directed changes in the RXR ligand scaffold can lead to selective formation of specific hetero- and homodimers. Using our structural data and focused compound library, a model was developed to help to understand this effect of the ligand. This information can serve as a blueprint to design small-molecules that selectively target specific NRs via RXR. This makes RXR as an exciting and versatile target for NR modulation, especially when classical modulation of the partner NR is not possible.
Recently, small-molecules have been found to bind to allosteric sites of NRs. Allosteric ligands are of interest since they do not compete with the endogenous ligand of the NR and often shown an increased selectivity towards their target. We show, using X-ray crystallography and biochemical assays, that there is communication between orthosteric and allosteric ligands in the RAR-related orphan receptor γ t (RORγt). We successfully solved eleven new ternary crystal structures of RORγt in the presence of both orthosteric and allosteric ligands. These structures mechanistically show how binding of the orthosteric ligand leads to positive cooperative binding of the allosteric ligand.

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(1) Eindhoven University of Technology, The Netherlands


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Best Poster Awards – Target Validation Using Genomics and Informatics

Meet Giovanni Spirito and Borja Gomez Ramos – the two poster prize winners at the recent EMBL – Wellcome Genome Campus Conference: Target Validation Using Genomics and Informatics (8 – 10 Dec 2019).

Identification and prioritization of candidate causal genomic variations from individuals affected by ASD

PHOTO: Giovanni Spirito

Authors: Giovanni Spirito (1), Diego Vozzi (2), Martina Servetti (3), Margherita Lerone (3), Maria Teresa Divizia (3), Giulia Rosti (3), Livia Pisciotta (4), Lino Nobili (4), Irene Serio (4), Stefano Gustincich (2), Remo Sanges (1)

Next generation sequencing (NGS) technologies enabled the extensive study of the genomics underlying human diseases. Namely whole exome sequencing (WES) represents a cost-efficient method which can lead to the detection of multiple classes of genomic variants and the discovery of novel disease-associated genes. One of the drawbacks of this approach however, is the large number of genomic variants detected in each analysis. Automated variant prioritization strategies are therefore required. This is particularly important in the case of complex disease such as ASD, whose genetic etiology is still poorly understood. To this aim we built a custom computational framework capable, from raw WES data, to automatically detect four classes of genomic variants (SNPs, indels, copy number variants and short tandem repeat variants) and prioritize them in regards to their relevance to a specific phenotype. We tested this framework on a selection of 29 trios including probands affected by severe and undiagnosed rare phenotypes and a small cohort of 10 trios all featuring healthy parents and one offspring affected by autism spectrum disorder (ASD). We were able to successfully detect rare and de novo high penetrance variants which have been validated and confirmed as causative among the undiagnosed probands. In the specific case of the ASD cohort we could highlight several genes which are not implicated in autism susceptibility, but nevertheless whose connections to genes relevant for ASD could suggest a possible involvement in the phenotype. Furthermore, our approach enabled us to detect several instances characterized by the presence of multiple candidate variants within genes belonging to the same canonical pathway in one proband. Our workflow allows to detect and prioritize multiple classes of genomic variants in order to both highlight rare high penetrance disease-causative mutation, and possibly reconstruct the genomics at the basis of complex ASD phenotypes.

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(1) SISSA, Italy, (2) IIT, Italy, (3) Gaslini Institute, Italy, (4) University of Genova, Italy


Omics data integration for the identification of cell-type-specific gene regulatory networks and regulatory variants in Parkinson’s disease

PHOTO: Borja Gomez Ramos

Authors: Borja Gomez Ramos (1,2), Jochen Ohnmacht (1,2), Nikola de Lange (2), Aurélien Ginolhac (1), Aleksandar Rakovic (5), Christine Klein (5), Roland Krause (2) , Marcel H. Schulz (6), Thomas Sauter (1), Rejko Krüger (2,3,4) and Lasse Sinkkonen (1)

Genome-Wide Association Studies (GWAS) have identified many variants associated with different diseases. However, it is still a challenge to make sense of this data as the majority of genetic variants are located in non-coding regions, complicating the understanding of their functionality. In the last few years, it has been found that non-coding genetic variants concentrate in regulatory regions in the genome, which are cell type and cell-stage specific. In this project, we seek to identify functional Parkinson’s disease GWAS non-coding genetic variants that could make carriers more prone to developing PD. To do so, we are using induced pluripotent stem cell (iPSC) technology to differentiate somatic cells into midbrain dopaminergic (mDA) neurons, astrocytes and microglia. Assessing their chromatin accessibility, active chromatin regions and transcriptome, we can identify crucial regulatory regions in the genome, key transcription factors and derive the gene regulatory networks for the three different cell types. Then, we will map the non-coding genetic variants to the different regulatory regions and predict their effect in silico for the subsequent validation in vitro. This innovative approach will also identify novel factors controlling cell fate and cell identity.

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(1) Life Sciences Research Unit, University of Luxembourg, Luxembourg, (2) Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, Luxembourg, (3) Centre Hospitalier de Luxembourg (CHL), Luxembourg, (4) Luxembourg Institute of Health (LIH), Luxembourg, (5) Institute of Neurogenetics, University of Lübeck, Germany, (6) Institute for Cardiovascular Regeneration, Uniklinikum and Goethe University Frankfurt, Germany


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