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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Best Poster Awards – Metabolism Meets Epigenetics

In its first edition, the EMBO|EMBL Symposium: Metabolism Meets Epigenetics brought together 289 world-leading researchers who examined how metabolites and metabolic networks impact gene regulation, what their roles are in disease and how this opens novel therapeutic avenues.

In addition to the 21 invited speakers and 22 selected short talks, 142 posters were presented during the two poster sessions. Today we present three of the five award-winning posters decided by popular vote.

Citrate carrier links intermediate metabolism to histone acetylation upon ageing of mouse mesenchymal stem cells (MSCs)

PHOTO: Andromachi Pouikli

Authors: Andromachi Pouikli (1), Monika Maleszewska (2), Swati Parekh (1), Chrysa Nikopoulou (1), Maarouf Baghdadi (1), Linda Partridge (1), Peter Tessarz (1)

Chromatin and metabolism interact in a reciprocal manner; on one hand metabolism-related genes are subjected to epigenetic modifications, which regulate gene expression. On the other hand, intracellular metabolism provides metabolites which can serve as essential co-factors and substrates for chromatin-modifying enzymes, affecting their activity. Although, it is well established that the process of ageing is accompanied by changes in metabolism and by chromatin alterations, their interplay in this context remains still poorly understood. In this study we sought to determine how ageing impinges on the relationship between cellular metabolism and the epigenome, using mouse mesenchymal stem cells from the bone marrow (BM-MSCs). In brief, our data suggest that there is a strong and direct link between the metabolic and the epigenetic states of the cell, with ageing-driven changes in metabolism regulating gene transcription and BM-MSC’s stemness, via alterations of the chromatin structure. We conclude that physiological ageing elicits changes in metabolism, resulting in suppressed glycolysis and impaired lipid biogenesis. Moreover, we demonstrate that during ageing there are lower levels of histone acetylation, despite the higher acetyl-CoA levels. We provide a solid explanation for this apparent discrepancy, pointing to the impaired export of acetyl-CoA from mitochondria to the cytosol. Indeed, the protein levels of the citrate carrier Slc25a1 decrease dramatically upon ageing. Using inhibition and supplementation experiments we provide a causal relationship between Slc25a1 function and the levels of histone acetylation, which directly influence chromatin accessibility and plasticity. Collectively, our data establish a tight, age-dependent connection between metabolism, epigenome and stemness and identify citrate carrier as the responsible protein for the mitochondrial-nuclear communication.

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(1) Max Planck Institute for Biology of Ageing, Germany, (2) Personalis Inc, Germany

Epigenetics meets metabolism through histone acetyltransferase NAA40

PHOTO: Christina Demetriadou

Authors: Christina Demetriadou (1), Anastasia Raoukka (1), Agathi Elpidoforou  (1), Constantine Mylonas (2), Swati Parekh (2), Peter Tessarz (2), Antonis Kirmizis (1)

N-alpha-acetyltransferase 40 (NAA40) is distinct among other histone acetyltransferases (HATs) because it deposits an acetyl moiety on the alpha-amino group at the very N-terminal tip of histones H4 and H2A, instead on the lysine side chain. The biological function of this evolutionarily conserved enzyme remained unexplored for several decades because it was thought to mediate an inert modification. However, we previously showed that NAA40-mediated N-terminal acetylation of histone H4 (N-acH4) crosstalks with an adjacent arginine methylation mark to regulate yeast cellular aging in response to caloric restriction through transcriptional control of several metabolic genes. Therefore, we are currently interested in deciphering the function of human NAA40 in carcinogenesis. We recently showed that NAA40 is frequently upregulated in primary human colorectal cancer (CRC) samples. Remarkably, depletion of NAA40 and its accompanied reduction in N-acH4 blocked colon cancer cell proliferation and reduced cell survival in vitro and in xenograft models. We also found that loss of NAA40 expression or of its HAT activity markedly induce global histone methylation. Additionally, whole transcriptome analysis showed that NAA40 knockdown leads to upregulation of key enzymes involved in one-carbon metabolism. Intriguingly, silencing of methylenetetrahydrofolate reductase (MTHFR), which links the folate to methionine cycle, rescues the induction of global histone methylation and loss of cell viability triggered by NAA40 depletion. Hence, this recent work implies that NAA40 may transcriptionally regulate vital metabolic enzymes to control the flux of carbon units into the methionine cycle influencing S-adenosylmethionine (SAM) levels and triggering epigenome reprogramming of cancer cells. Overall, our findings thus far propose that NAA40 and its associated N-acH4 are crucial epigenetic modulators in tumourigenesis and implicate these factors in rewiring cancer cell metabolism.

Poster currently not available.

(1) University of Cyprus, Cyprus
(2) Max Planck Institute for Biology of Ageing, Germany

Role of MOF acetyl transferase in mitochondrial homeostasis

PHOTO: Sukanya Guhathakurta

Authors: Sukanya Guhathakurta (1), Christoph Martensson (2), Alexander Schendzielorz (3), Bettina Warsheid (3), Thomas Becker (2), Asifa Akhtar (1)

Mitochondria lies at the centre of cellular and organismal energy homeostasis, housing a large repertoire of enzymes that are required for the synergy of various metabolic pathways. Mitochondrial gene expression and protein acetylation are two important fundamental processes situated at the crossroad between mitochondrial function and metabolic status of a cell. Gene transcription in the mitochondria has been studied over several decades, but enzymatic acetylation of mitochondria proteins has stayed so far enigmatic. MOF acetyl transferase and its KANSL complex members dually localize to the nucleus and the mitochondria in mouse and human cells. The MOF-KANSL complex regulates metabolic gene transcription in the nucleus and expression of Electron Transport Chain (mtETC) components from the mtDNA, in a cell type dependent fashion. Regulation of nuclear gene transcription by MOF is well understood, however, its control of mitochondrial function remains elusive. Here, we report that loss of MOF leads to severe mitochondrial dysfunction in Mouse Embryonic Fibroblasts (MEFs), sprouting from a stalled oxidative phosphorylation. We address the mechanisms by which the enzyme maintains mitochondrial function in these cells by using a multi-omics approach. We discovered that the role of MOF-KANSL complex in the mitochondria of aerobically respiring cells could be decoupled from its regulation of steady state RNA levels, and could further be attributed to the acetylation of mitochondrial proteins. We characterize the role of acetylation on these proteins through generation of acetylated and non-acetylated mimics. Collectively our data, along with previously published works, suggests that MOF has emerged as a moderator to strike a harmony in the context of communication between the nucleus and the mitochondria. Recent progress on the project will be discussed.

(1) Max Planck Institute for Immunobiology and Epigenetics, Germany
(2) Institute of Biochemistry and Molecular Biology, Germany
(3) Institute for Biology II, Germany

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Meet the Trainer – María del Mar Vivanco

PHOTO: María del Mar Vivanco

Meet María del Mar Vivanco, Team Leader at CIC bioGUNE in Bilbao, Spain. Maria is one of the organisers of the EMBO Practical Course: Techniques for Mammary Gland Research (1 – 6 March 2020).

What is your research focus?

I am interested in cancer heterogeneity, why some cells respond to therapy while others do not, thus contributing to development of resistance and metastasis. In particular, I am intrigued about the complex effects of transcription factors, which are required for normal physiology of the mammary gland and are also implicated in tumorigenesis and development of resistance to therapy in breast cancer.

Why did you choose to become a scientist?

When I was young I had a variety of interests – psychology, physics, art, biology… However, I was intrigued by science and anything related to DNA and its regulation. Then I did my PhD at EMBL Heidelberg (Gene Expression Programme) and discovered the opportunities in research for identifying problems, looking for solutions and the thrill of finding some of the answers…and I was hooked!

Where do you see this field heading in the future?

Despite significant progress in cancer research and clinical advances, breast cancer still is the most commonly diagnosed cancer – one in eight women will develop this disease during their lifetime – and it claims the lives of more women than any other cancer, plus men can also get breast cancer. This highlights the unmet clinical need for improved strategies for prevention, early detection and more efficient and specific treatments in order to accelerate progress and help more patients survive the disease.

One of the features that characterises breast cancer is its heterogeneity, both among patients and within each patient tumor. This heterogeneity is found at molecular, phenotypic and functional levels, complicating diagnosis and challenging approaches to therapy. Currently, huge efforts are dedicated to understanding this heterogeneity at all levels, including at single-cell resolution, which is anticipated to open new possibilities for more efficient and specific anti-cancer therapies.

How has training influenced your career? 

Doing my PhD at EMBL marked the way I envision science, and this vision was reinforced and developed further at UCSF. Science can – and SHOULD – be fun. Later on, funding struggles and the current publishing madness have somehow taken a toll on the fun element, so I just have to remind myself sometimes that science is still exciting!

If you weren’t a scientist, what would you be?

An artist.

You are one of the organisers of the EMBO Practical Course: Techniques for Mammary Gland Research (1 – 6 March 2020). What is the greatest benefit of the course for the scientific community and what could the techniques in this course be used for in the bigger picture?

Some of the techniques practiced at this course are specific for the mammary gland and thus it provides a solid base for researchers starting in this field. In addition, there is a significant emphasis on imaging and comparison of mouse and human studies, the two major systems for looking at normal physiology and cancer research that, when combined, offer great insights into this heterogeneous disease. In addition, having the opportunity to work alongside other trainees contributes to the establishment of a network that may be helpful in the future. Cancer is a very complex problem, and having collaborators with different views and expertise will be very useful in your career.

Interested in this course? Submit your application by 8 December!

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Best Poster Awards – Cancer Genomics

The 4th EMBL Conference: Cancer Genomics (4 – 6 November 2019) brought together over 240 scientists in the field of cancer research to present the latest findings in cancer functional genomics, systems biology, cancer immunogenomics and epigenomics, as well as their translation and clinical impact.

123 posters were presented at the two poster sessions, out of which two were selected as the winners by popular vote. 

Infinite sites violations during tumour evolution reveal local mutational determinants

Jonas Demeulemeester is a postdoctoral researcher at the Francis Crick Insitute in UK. PHOTO: Jonas Demeulemeester

Authors: Jonas Demeulemeester (1), Stefan C. Dentro (2), Moritz Gerstung (2), Peter Van Loo (1)

The infinite sites model of molecular evolution requires that every base in the genome is mutated at most once. It is a cornerstone of (tumour) phylogenetic analysis, and is often implied when calling, phasing and interpreting variants or studying the mutational landscape as a whole. It is unclear however, whether this assumption holds in practice for bulk tumour samples. Here we provide frameworks to model and detect infinite sites violations, identifying 24,459 in total, including 6 candidate biallelic driver events, in 700 bulk tumour samples (26.3%) from the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes project. Violations generally occur at mutational hotspots and their frequency and type can accurately be predicted from the overall mutation spectrum. In melanoma, their local sequence context evidences how not only ETS, but also NFAT-family transcription factor binding creates hotspots for UV-induced cyclobutane pyrimidine dimer formation. In colorectal adenocarcinoma, violations reveal hypermutable special cases of the trinucleotide mutational contexts identified in POLE-mutant tumours. Taken together, we reveal the infinite sites model breaks down at the bulk level for a considerable fraction of tumours. These results warrant a careful evaluation of current pipelines relying on the validity of the infinite sites assumption, especially when scaling up to larger sets of mutations and lineages in the future.

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(1) The Francis Crick Institute, United Kingdom, (2) EMBL-EBI, United Kingdom

The other award-winning poster was:

Understanding the early impact of activating PIK3CA mutation on cellular and genetic heterogeneity presented by Evelyn Lau, UCL Cancer Institute, United Kingdom

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Meet the Trainer – Pavel Baranov

Meet Pavel Baranov, Professor of Biomolecular Informatics at the University College Cork, Ireland. Pavel’s research group focuses on the understanding of how proteins are synthesised and how their synthesis is regulated.

Why did you choose to become a scientist?

When I was a toddler, I wanted to be a firefighter. Within a couple of years, I decided that being an astronaut would be more fun. A few more years passed, and I began to dream of becoming a scientist. I guess at that point I stopped growing and started living my dream.

What is your research focus?

My research group studies RNA translation. Translation is at the core of biology. Cells spend most of their energy on protein synthesis and the ribosome is the most abundant molecular machine in almost all cells. Ribosomal RNAs and tRNAs are the most conserved molecules across all kingdoms of life, and it is now apparent that proteins evolved earlier than DNA. Life as we know it relies on two main type of molecules not found outside of living systems – nucleic acids and proteins. It is the process of translation that connects these two chemistries together. I could hardly think of a more fundamental, interesting and challenging cellular process than translation.

Where do you see this field heading in the future?

As translation brings two chemistries together it is far more complex than other molecular process such as transcription and replication. Because of its complexity and the lack of tools to study it, studying translation is very challenging. The tools are now being developed, e.g. variations of ribosome profiling techniques, real-time single molecule imaging, cryo-EM microscopy, etc. The main change that I foresee is that translation will draw the attention of many more biomedical researchers, for better or worse.

What is your number one tip for people looking for scientific training?

Independent practice is the key in my opinion. After taking a course you may get the impression that you can do something, but it could be a false impression – you don’t really know if you can unless you have done it.

If you weren’t a scientist, what would you be?

Science is not a job for me, it is a dream. If I were not able to make my living as a researcher, I would have to find something else to make earnings, but I would not give up on my scientific interests.

You are organising the EMBO Practical Course ”Measuring Translational Dynamics by Ribosome Profiling” (3 – 9 May 2020). What is the greatest benefit of the course for the scientific community and what could the techniques in this course be used for in the bigger picture?

The invention of ribosome profiling is the most significant development in the field of protein synthesis since the deciphering of the ribosome 3D structure. Ribosomal profiling is a popular technique for measuring the rate of translation in addition to measuring RNA levels, but this was somewhat possible even before. The unique ability of ribosome profiling is the detection of which open reading frames are being translated in RNA. The application of ribosome profiling revealed that even in eukaryotes the same mRNA molecule is often used for making more than one polypeptide, and that our current knowledge of the human genome protein coding repertoire is still far from complete. In addition to detecting translated frames, ribosome profiling could be used to detect ribosome pauses.  We recently learned that such pauses could be used to regulate gene expression and other biological processes.  This course will provide trainees with everything what is needed for mastering this powerful technology, from hands-on experience in generating ribosome profiling data to bioinformatics analysis and the use of public data resources.

Interested in this course? Submit your application by 9 February!

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