Research Center for Molecular Medicine

Vienna, Austria

Research Center for Molecular Medicine

Vienna, Austria

Time filter

Source Type

Herzog V.A.,IMBA Institute of Molecular Biotechnology | Lempradl A.,IMBA Institute of Molecular Biotechnology | Lempradl A.,Max Planck Institute of Immunobiology and Epigenetics | Trupke J.,IMBA Institute of Molecular Biotechnology | And 15 more authors.
Nature Genetics | Year: 2014

Polycomb/Trithorax response elements (PRE/TREs) can switch their function reversibly between silencing and activation by mechanisms that are poorly understood. Here we show that a switch in forward and reverse noncoding transcription from the Drosophila melanogaster vestigial (vg) PRE/TRE switches the status of the element between silencing (induced by the forward strand) and activation (induced by the reverse strand). In vitro, both noncoding RNAs inhibit PRC2 histone methyltransferase activity, but, in vivo, only the reverse strand binds PRC2. Overexpression of the reverse strand evicts PRC2 from chromatin and inhibits its enzymatic activity. We propose that the interaction of RNAs with PRC2 is differentially regulated in vivo, allowing regulated inhibition of local PRC2 activity. Genome-wide analysis shows that strand switching of noncoding RNAs occurs at several hundred Polycomb-binding sites in fly and vertebrate genomes. This work identifies a previously unreported and potentially widespread class of PRE/TREs that switch function by switching the direction of noncoding RNA transcription. © 2014 Nature America, Inc. All rights reserved.


Gyongyosi A.,Research Center for Molecular Medicine | Szatmari I.,Research Center for Molecular Medicine | Pap A.,Research Center for Molecular Medicine | Dezso B.,Mta Of Lendulet Immungenomics Research Group | And 6 more authors.
Journal of Lipid Research | Year: 2013

All- trans retinoic acid (ATRA) has a key role in dendritic cells (DCs) and affects T cell subtype specification and gut homing. However, the identity of the permissive cell types and the required steps of conversion of vitamin A to biologically active ATRA bringing about retinoic acid receptor-regulated signaling remains elusive. Here we present that only a subset of murine and human DCs express the necessary enzymes, including RDH10, RALDH2, and transporter cellular retinoic acid binding protein (CRABP)2, to produce ATRA and efficient signaling. These permissive cell types include CD103+ DCs, granulocyte-macrophage colonystimulating factor, and interleukin-4-treated bone marrowderived murine DCs and human monocyte-derived DCs (mo-DCs). Importantly, in addition to RDH10 and RALDH2, CRABP2 also appears to be regulated by the fatty acid-sensing nuclear receptor peroxisome proliferator-activated receptor γ (PPAR γ ) and colocalize in human gut-associated lymphoid tissue DCs. In our model of human mo-DCs, all three proteins (RDH10, RALDH2, and CRABP2) appeared to be required for ATRA production induced by activation of PPARγ and therefore form a linear pathway. This now functionally validated PPARγ-regulated ATRA producing and signaling axis equips the cells with the capacity to convert precursors to active retinoids in response to receptor-activating fatty acids and is potentially amenable to intervention in diseases involving or affecting mucosal immunity. Copyright © 2013 by the American Society for Biochemistry and Molecular Biology, Inc.


PubMed | University of Minnesota, 1 IMBA Institute of Molecular Biotechnology, Research Center for Molecular Medicine, IMP Institute of Molecular Pathology and 3 more.
Type: Journal Article | Journal: Nature genetics | Year: 2014

Polycomb/Trithorax response elements (PRE/TREs) can switch their function reversibly between silencing and activation by mechanisms that are poorly understood. Here we show that a switch in forward and reverse noncoding transcription from the Drosophila melanogaster vestigial (vg) PRE/TRE switches the status of the element between silencing (induced by the forward strand) and activation (induced by the reverse strand). In vitro, both noncoding RNAs inhibit PRC2 histone methyltransferase activity, but, in vivo, only the reverse strand binds PRC2. Overexpression of the reverse strand evicts PRC2 from chromatin and inhibits its enzymatic activity. We propose that the interaction of RNAs with PRC2 is differentially regulated in vivo, allowing regulated inhibition of local PRC2 activity. Genome-wide analysis shows that strand switching of noncoding RNAs occurs at several hundred Polycomb-binding sites in fly and vertebrate genomes. This work identifies a previously unreported and potentially widespread class of PRE/TREs that switch function by switching the direction of noncoding RNA transcription.


News Article | November 17, 2016
Site: www.eurekalert.org

Scientists have established comprehensive maps of the human epigenome, shedding light on how the body regulates which genes are active in which cells. Over the last five years, a worldwide consortium of scientists has established epigenetic maps of 2,100 cell types. Within this coordinated effort, the CeMM Research Center for Molecular Medicine contributed detailed DNA methylation maps of the developing blood, opening up new perspectives for the understanding and treatment of leukemia and immune diseases. One of the great mysteries in biology is how the many different cell types that make up our bodies are derived from a single cell and from one DNA sequence, or genome. We have learned a lot from studying the human genome, but have only partially unveiled the processes underlying cell determination. The identity of each cell type is largely defined by an instructive layer of molecular annotations on top of the genome - the epigenome - which acts as a blueprint unique to each cell type and developmental stage. Unlike the genome the epigenome changes as cells develop and in response to changes in the environment. Defects in the factors that read, write, and erase the epigenetic blueprint are involved in many diseases. The comprehensive analysis of the epigenomes of healthy and abnormal cells will facilitate new ways to diagnose and treat various diseases, and ultimately lead to improved health outcomes. A collection of 41 coordinated papers now published by scientists from across the International Human Epigenome Consortium (IHEC) sheds light on these processes, taking global research in the field of epigenomics a major step forward. These papers represent the most recent work of IHEC member projects from Canada, the European Union, Germany, Japan, Singapore, South Korea, and the United States. Three of these papers have been coordinated by Christoph Bock at CeMM. The latest study from Christoph Bock's team, published today in the journal Cell Stem Cell, charts the epigenetic landscape of DNA methylation in human blood. Led by CeMM scientists Matthias Farlik and Florian Halbritter together with Fabian Müller from Max Plank Institute for Informatics, this study highlights the dynamic nature of the epigenome in the development of human blood. Our body produces billions of blood cells every day, which develop from a few thousand stem cells at the top of a complex hierarchy of blood cells. Using the latest sequencing and epigenome mapping technology, Bock's team now unraveled a blueprint of blood development that is encoded in the DNA methylation patterns of blood stem cells and their differentiating progeny. This success was made possible by close international cooperation of European scientists: Blood donations of British volunteers were sorted by cell type by the team of Mattia Frontini at the University of Cambridge. These samples were shipped to Austria, where CeMM scientists performed the epigenome mapping. All data were then processed in Germany at the Max Plank Institute for Informatics and jointly analyzed by scientists at CeMM and at the Max Plank Institute for Informatics. The result of the combined effort of Bock's team and many other members of IHEC is a detailed map of the human epigenome, similar to a three-dimensional mountain landscape: The stem cells reside on the mountain top, with valleys of cellular differentiation descending in many directions. As the cells differentiate, they pick one of several epigenetically defined routes and follow it downhill, eventually arriving at one specific valley, corresponding to a specialized cell type. Cells cannot easily escape these valleys, which provides robustness and protection against diseases such cancer. Two other studies by Christoph Bock's team were published earlier this year and showcase how researchers are seeking to utilize epigenetic information for medicine. For instance, certain routes of differentiation are jammed in leukemia, such that cells can no longer reach their destination and take wrong turns instead. Surveillance of those cells by epigenetic tests can contribute to a more precise diagnosis of leukemia - clinical tests of this approach are ongoing. „The epigenetic map of the human blood helps us understand how leukemia develops and which cells drive the disease" says Christoph Bock. This is relevant to cancer diagnostics and personalized medicine, and it provides a compass for future efforts aiming to reprogram the epigenome of individual cells, for example by erasing critical epigenetic alterations from leukemia cells. "The collection of manuscripts released by IHEC impressively demonstrates how epigenetic information and analyses can help find answers to pressing questions related to the cellular mechanisms associated with complex human diseases", said Professor Hendrik (Henk) Stunnenberg from Radboud University, The Netherlands, former Chair of the IHEC International Scientific Steering Committee and coordinator of the EU-funded BLUEPRINT project. The Study "DNA Methylation Dynamics of Human Hematopoietic Stem Cell Differentiation" is published on 17 November 2016 in Cell Stem Cell, DOI:10.1016/j.stem.2016.10.019 Funding: This study was partly funded by the BLUEPRINT Project of the European Union. Christoph Bock is a Principal Investigator at CeMM. Trained as a bioinformatician, he leads a team that integrates biology, medicine, and computer science - working on a vision of precision medicine that is driven by large datasets and a deep understanding of disease mechanisms. He is also a guest professor at the Medical University of Vienna's Department for Laboratory Medicine, and he coordinates the genome sequencing activities of CeMM and the Medical University of Vienna. At CeMM, he co-initiated and leads Genom Austria, the Austrian contribution to the International Network of Personal Genome Projects, and he is a principal investigator in the BLUEPRINT project and the International Human Epigenome Consortium. CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences is an interdisciplinary research institute committed to advancing the understanding of human diseases through basic and biomedical research. Located at the center of the Medical University of Vienna's campus, CeMM fosters a highly collaborative and interactive research mindset. Focusing on medically relevant questions, CeMM researchers concentrate on human biology and diseases like cancer and inflammation/immune disorders. In support of scientific pursuits and medical needs, CeMM provides access to cutting-edge technologies and has established a strategic interest in personalized medicine. Since 2005, Giulio Superti-Furga is the Scientific Director of CeMM. The project BLUEPRINT - A BLUEPRINT of Haematopoietic Epigenomes is a large-scale research project receiving close to 30 million Euro funding from the EU. 42 leading European universities, research institutes and industry entrepreneurs participate in what is one of the two first so-called high impact research initiatives to receive funding from the EU. For more information, please visit: The International Human Epigenome Consortium (IHEC) is a global consortium with the primary goal of providing free access to high-resolution reference human epigenome maps for normal and disease cell types to the research community. IHEC members support related projects to improve epigenomic technologies, investigate epigenetic regulation in disease processes, and explore broader gene-environment interactions in human health. Current full members of IHEC include: AMED-CREST/IHEC Team Japan; DLR-PT for BMBF German Epigenome Programme DEEP; CIHR Canadian Epigenetics Environment, and Health Research Consortium (CEEHRC); European Union FP7 BLUEPRINT Project; Hong Kong Epigenomics Project; KNIH Korea Epigenome Project; the NIH/NHGRI ENCODE Project; the NIH Roadmap Epigenomics Program; and the Singapore Epigenome Project. For more information, please visit: For further information please contact Mag. Wolfgang Däuble Media Relations Manager CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences Lazarettgasse 14, AKH BT 25.3 1090 Vienna, Austria Phone +43-1/40160-70 057 Fax +43-1/40160-970 000 wdaeuble@cemm.oeaw.ac.at http://www.


PubMed | Research Center for Molecular Medicine, University of Hamburg, French Institute of Health and Medical Research, Charité - Medical University of Berlin and 3 more.
Type: | Journal: Leukemia | Year: 2016

Children with P2RY8-CRLF2-positive acute lymphoblastic leukemia have an increased relapse risk. Their mutational and transcriptional landscape, as well as the respective patterns at relapse remain largely elusive. We, therefore, performed an integrated analysis of whole-exome and RNA sequencing in 41 major clone fusion-positive cases including 19 matched diagnosis/relapse pairs. We detected a variety of frequently subclonal and highly instable JAK/STAT but also RTK/Ras pathway-activating mutations in 76% of cases at diagnosis and virtually all relapses. Unlike P2RY8-CRLF2 that was lost in 32% of relapses, all other genomic alterations affecting lymphoid development (58%) and cell cycle (39%) remained stable. Only IKZF1 alterations predominated in relapsing cases (P=0.001) and increased from initially 36 to 58% in matched cases. IKZF1s critical role is further corroborated by its specific transcriptional signature comprising stem cell features with signs of impaired lymphoid differentiation, enhanced focal adhesion, activated hypoxia pathway, deregulated cell cycle and increased drug resistance. Our findings support the notion that P2RY8-CRLF2 is dispensable for relapse development and instead highlight the prominent rank of IKZF1 for relapse development by mediating self-renewal and homing to the bone marrow niche. Consequently, reverting aberrant IKAROS signaling or its disparate programs emerges as an attractive potential treatment option in these leukemias.Leukemia advance online publication, 6 January 2017; doi:10.1038/leu.2016.365.


PubMed | Hannover Medical School, University of Milan Bicocca, Research Center for Molecular Medicine, University of Hamburg and 5 more.
Type: Comparative Study | Journal: Leukemia | Year: 2015

High hyperdiploidy defines the largest genetic entity of childhood acute lymphoblastic leukemia (ALL). Despite its relatively low recurrence risk, this subgroup generates a high proportion of relapses. The cause and origin of these relapses remains obscure. We therefore explored the mutational landscape in high hyperdiploid (HD) ALL with whole-exome (n=19) and subsequent targeted deep sequencing of 60 genes in 100 relapsing and 51 non-relapsing cases. We identified multiple clones at diagnosis that were primarily defined by a variety of mutations in receptor tyrosine kinase (RTK)/Ras pathway and chromatin-modifying genes. The relapse clones consisted of reappearing as well as new mutations, and overall contained more mutations. Although RTK/Ras pathway mutations were similarly frequent between diagnosis and relapse, both intergenic and intragenic heterogeneity was essentially lost at relapse. CREBBP mutations, however, increased from initially 18-30% at relapse, then commonly co-occurred with KRAS mutations (P<0.001) and these relapses appeared primarily early (P=0.012). Our results confirm the exceptional susceptibility of HD ALL to RTK/Ras pathway and CREBBP mutations, but, more importantly, suggest that mutant KRAS and CREBBP might cooperate and equip cells with the necessary capacity to evolve into a relapse-generating clone.


O'Sullivan R.J.,Salk Institute for Biological Studies | Kubicek S.,Cambridge Broad Institute | Kubicek S.,Research Center for Molecular Medicine | Schreiber S.L.,Cambridge Broad Institute | And 3 more authors.
Nature Structural and Molecular Biology | Year: 2010

During replicative aging of primary cells morphological transformations occur, the expression pattern is altered and chromatin changes globally. Here we show that chronic damage signals, probably caused by telomere processing, affect expression of histones and lead to their depletion. We investigated the abundance and cell cycle expression of histones and histone chaperones and found defects in histone biosynthesis during replicative aging. Simultaneously, epigenetic marks were redistributed across the phases of the cell cycle and the DNA damage response (DDR) machinery was activated. The age-dependent reprogramming affected telomeric chromatin itself, which was progressively destabilized, leading to a boost of the telomere-associated DDR with each successive cell cycle. We propose a mechanism in which changes in the structural and epigenetic integrity of telomeres affect core histones and their chaperones, enforcing a self-perpetuating pathway of global epigenetic changes that ultimately leads to senescence. © 2010 Nature America, Inc. All rights reserved.


News Article | November 18, 2016
Site: www.sciencedaily.com

Scientists have established comprehensive maps of the human epigenome, shedding light on how the body regulates which genes are active in which cells. Over the last five years, a worldwide consortium of scientists has established epigenetic maps of 2,100 cell types. Within this coordinated effort, the CeMM Research Center for Molecular Medicine contributed detailed DNA methylation maps of the developing blood, opening up new perspectives for the understanding and treatment of leukemia and immune diseases. One of the great mysteries in biology is how the many different cell types that make up our bodies are derived from a single cell and from one DNA sequence, or genome. We have learned a lot from studying the human genome, but have only partially unveiled the processes underlying cell determination. The identity of each cell type is largely defined by an instructive layer of molecular annotations on top of the genome -- the epigenome -- which acts as a blueprint unique to each cell type and developmental stage. Unlike the genome the epigenome changes as cells develop and in response to changes in the environment. Defects in the factors that read, write, and erase the epigenetic blueprint are involved in many diseases. The comprehensive analysis of the epigenomes of healthy and abnormal cells will facilitate new ways to diagnose and treat various diseases, and ultimately lead to improved health outcomes. A collection of 41 coordinated papers now published by scientists from across the International Human Epigenome Consortium (IHEC) sheds light on these processes, taking global research in the field of epigenomics a major step forward. These papers represent the most recent work of IHEC member projects from Canada, the European Union, Germany, Japan, Singapore, South Korea, and the United States. Three of these papers have been coordinated by Christoph Bock at CeMM. The latest study from Christoph Bock's team, published today in the journal Cell Stem Cell, charts the epigenetic landscape of DNA methylation in human blood. Led by CeMM scientists Matthias Farlik and Florian Halbritter together with Fabian Müller from Max Plank Institute for Informatics, this study highlights the dynamic nature of the epigenome in the development of human blood. Our body produces billions of blood cells every day, which develop from a few thousand stem cells at the top of a complex hierarchy of blood cells. Using the latest sequencing and epigenome mapping technology, Bock's team now unraveled a blueprint of blood development that is encoded in the DNA methylation patterns of blood stem cells and their differentiating progeny. This success was made possible by close international cooperation of European scientists: Blood donations of British volunteers were sorted by cell type by the team of Mattia Frontini at the University of Cambridge. These samples were shipped to Austria, where CeMM scientists performed the epigenome mapping. All data were then processed in Germany at the Max Plank Institute for Informatics and jointly analyzed by scientists at CeMM and at the Max Plank Institute for Informatics. The result of the combined effort of Bock's team and many other members of IHEC is a detailed map of the human epigenome, similar to a three-dimensional mountain landscape: The stem cells reside on the mountain top, with valleys of cellular differentiation descending in many directions. As the cells differentiate, they pick one of several epigenetically defined routes and follow it downhill, eventually arriving at one specific valley, corresponding to a specialized cell type. Cells cannot easily escape these valleys, which provides robustness and protection against diseases such cancer. Two other studies by Christoph Bock's team were published earlier this year and showcase how researchers are seeking to utilize epigenetic information for medicine. For instance, certain routes of differentiation are jammed in leukemia, such that cells can no longer reach their destination and take wrong turns instead. Surveillance of those cells by epigenetic tests can contribute to a more precise diagnosis of leukemia -- clinical tests of this approach are ongoing. "The epigenetic map of the human blood helps us understand how leukemia develops and which cells drive the disease," says Christoph Bock. This is relevant to cancer diagnostics and personalized medicine, and it provides a compass for future efforts aiming to reprogram the epigenome of individual cells, for example by erasing critical epigenetic alterations from leukemia cells.


Babak M.V.,University of Auckland | Babak M.V.,University of Vienna | Meier S.M.,University of Vienna | Huber K.V.M.,Research Center for Molecular Medicine | And 13 more authors.
Chemical Science | Year: 2015

The clinical development of anticancer metallodrugs is often hindered by the elusive nature of their molecular targets. To identify the molecular targets of an antimetastatic ruthenium organometallic complex based on 1,3,5-triaza-7-phosphaadamantane (RAPTA), we employed a chemical proteomic approach. The approach combines the design of an affinity probe featuring the pharmacophore with mass-spectrometry-based analysis of interacting proteins found in cancer cell lysates. The comparison of data sets obtained for cell lysates from cancer cells before and after treatment with a competitive binder suggests that RAPTA interacts with a number of cancer-related proteins, which may be responsible for the antiangiogenic and antimetastatic activity of RAPTA complexes. Notably, the proteins identified include the cytokines midkine, pleiotrophin and fibroblast growth factor-binding protein 3. We also detected guanine nucleotide-binding protein-like 3 and FAM32A, which is in line with the hypothesis that the antiproliferative activity of RAPTA compounds is due to induction of a G2/M arrest and histone proteins identified earlier as potential targets. This journal is © The Royal Society of Chemistry.


Dancik V.,The Broad Institute of MIT and Harvard | Dancik V.,Slovak Academy of Sciences | Carrel H.,The Broad Institute of MIT and Harvard | Bodycombe N.E.,The Broad Institute of MIT and Harvard | And 7 more authors.
Journal of Biomolecular Screening | Year: 2014

High-throughput screening allows rapid identification of new candidate compounds for biological probe or drug development. Here, we describe a principled method to Generate "assay performance profiles" for individual compounds that can serve as a basis for similarity searches and cluster analyses. Our method overcomes three challenges associated with Generating robust assay performance profiles: (1) we transform data, allowing us to build profiles from assays having diverse dynamic ranges and variability; (2) we apply appropriate mathematical principles to handle missing data; and (3) we mitigate the fact that loss-of-signal assay measurements may not distinguish between multiple mechanisms that can lead to certain phenotypes (e.g., cell death). Our method connected compounds with similar mechanisms of action, enabling prediction of new targets and mechanisms both for known bioactives and for compounds emerging from new screens. Furthermore, we used Bayesian modeling of promiscuous compounds to distinguish between broadly bioactive and narrowly bioactive compound communities. Several examples illustrate the utility of our method to support mechanism-of-action studies in probe development and target identification projects. ©© 2014 Society for Laboratory Automation and Screening.

Loading Research Center for Molecular Medicine collaborators
Loading Research Center for Molecular Medicine collaborators