Interview mit Professor Christoph Dieterich vom Klaus-Tschira-Institut für Integrative Computerkardiologie
Heidelberg, 26. Januar 2022. Noch immer sind Erkrankungen von Herz und Kreislauf weltweit Todesursache Nummer eins. Das zu ändern, braucht einen langen Atem und sehr viel Grundlagenforschung. Für beides steht das Klaus-Tschira-Institut für Integrative Computerkardiologie des Universitätsklinikums Heidelberg. In den ersten fünf Jahren hat es sich zu einem Zentrum für kardiale, computergestützte Forschung entwickelt. Möglich ist dies durch interdisziplinäre Zusammenarbeit von Molekularbiologie, Bioinformatik und medizinischer Wissenschaft. Wie die nächsten Ziele aussehen, erklärt der Leiter des Instituts und Professor der Bioinformatik, Christoph Dieterich.
Heidelberg, 24.09.2020. Expertinnen und Experten des Deutschen Zentrums für Herz-Kreislauferkrankungen (DZHK) und des HiGHmed-Konsortiums der Medizininformatik-Initiative diskutierten beim ersten DZHK-HiGHmed-Symposium am 21. und 22. September 2020 in Heidelberg über innovative Ansätze für die Kardiologie.
Die Verknüpfung von unterschiedlichen Daten aus der Bildgebung, der molekularen Diagnostik und elektronischen Patientenakten auch mit Informationen, die Patientinnen und Patienten mittels tragbarer Sensoren im Alltag selbst erfassen, stellen das traditionelle Gesundheitswesen im Zeitalter der Digitalisierung vor neue Herausforderungen. „Unser Ziel ist es, das vielfältige Potenzial der Digitalisierung zu verdeutlichen und zum Wohle der Patientinnen und Patienten zu nutzen“, sagte Prof. Dr. Christoph Dieterich, Organisator des Symposiums und Leiter des Klaus Tschira Institute for Computational Cardiology am Universitätsklinikums Heidelberg zu Beginn der Veranstaltung.
Der gemeinsame Dialog zwischen Medizin und Informatik ist essentiell, um die Digitalisierung der Medizin voranzubringen. So wurden unter dem Titel „Cardiology meets Systems Medicine and Digital Health Solutions“ zum Beispiel neue Verfahren des maschinellen Lernens auf bildbasierten Daten und medizinischen Texten sowie die computergestützte Erweiterung der Realitätswahrnehmung in der medizinischen Lehre und im Behandlungskontext erörtert. Ein weiterer Programmteil befasste sich eingehend mit der Nutzung molekularer Techniken wie der Einzelzellanalyse, um individualisierte Ansätze in der Diagnostik, Prognostik und Therapie zu ermöglichen, etwa bei der Rekonstruktion von Herzgewebe nach einem Infarkt. In der abschließenden Sitzung wurde das Zusammenführen von heterogenen Datenquellen und deren gemeinsame Modellierung ausführlich diskutiert.
Das Symposium fand sowohl als Präsenzmeeting als auch als Webinar statt und wurde per Livestream übertragen. Interessierte konnten sich im Vorfeld registrieren und sich über eine Chatfunktion mit ihren Fragen interaktiv beteiligen. Rund 100 Zuschauer konnten dadurch an der Veranstaltung teilnehmen.
Link: https://www.medizininformatik-initiative.de/de/innovative-ansaetze-fuer-die-kardiologie
Posted on October 2020 by Etienne Boileau
In this study, we adopted a systems biology approach to integrate multi-omics data through the use of co-expression networks to highlight higher-order relationships among gene programs that are expressed
in the heart in vivo during the early stages of cardiac remodeling. Our analysis of 15 mouse left ventricular tissues from experimental models of exercise- and disease-induced cardiac hypertrophy showed, for the first time, the organization of the transcriptome and translatome into networks of biologically meaningful clusters of co-expressed genes. In contrast to differential expression analysis, co-expression and rewiring analysis led us to the identification of yet uncharacterized candidate genes, key to organizing the behaviour of transcriptome and translatome networks. In particular, our results uncovered Fam210a, a novel musculoskeletal modulator, which we hypothesize to regulate the expression of mitochondrial encoded genes; and Psmd12, a regulatory subunit of the 26S proteasome, whose deregulation may act as a pathogenic factor compromising protein quality control in cardiomyocytes. Our results constitute a valuable resource to study in vivo cardiac regulatory networks, and a first step towards the identification and characterization of novel proteins involved in cardiac remodeling, hypertrophy and heart failure.
Link: https://www.frontiersin.org/articles/10.3389/fgene.2020.583124
Posted on October 2020 by Etienne Boileau
The pig has emerged as an essential cardiovascular disease model, because its heart, circulatory system, and blood supply are anatomically and functionally similar to that of humans. It is becoming indispensable for cardiovascular research, clinically relevant proof of concept studies and for novel therapeutic interventions. In this work, we employed Nanopore long-read sequencing and in-depth proteomics on top of Illumina RNA-seq to enhance the pig cardiac transcriptome annotation. We predicted coding and non-coding transcripts via an integrated workflow. Our transcriptome assembly is combined with the existing two large databases, Ensembl and NCBI, and validated by a large-scale TMT mass-spectrometry data set, which was collected from 6 adult pig hearts across different left ventricular regions to sample the cardiac proteome diversity. All our data are available for download and are provided as tracks for integration in genome browsers. We deem this resource as highly valuable for molecular research in an increasingly relevant large animal model.
Link: https://www.jmmc-online.com/article/S0022-2828(20)30300-X/fulltext#st0120
New publication: Deep Characterization of Circular RNAs from Human Cardiovascular Cell Models and Cardiac Tissue
Posted on July 2020 by Tobias Jakobi
Our new study was undertaken to help to uncover potential functions of circular RNAs (circRNAs) that are relevant in cardiovascular disease (CVD) in cardiac model systems and organisms. The study defines a strongly conserved core set of circRNAs in human heart tissue, human induced pluripotent stem cell-derived cardiac myocytes (hiPSC-CMs), as well as mouse and pig heart. These circRNAs are promising potential targets for further studies because their function is likely conserved and therefore may be important in development and progression of CVD.
We employed a specialized deep sequencing approach to generate comprehensive maps of circRNA exon composition in hiPSC-CMs, human umbilical vein cells (HUVECs), and human hearts, which are required for more confident functional studies.
We identified shared circRNAs across all samples, as well as model-specific circRNA signatures and moreover identified a core set of positionally conserved and expressed circRNAs in human, pig, and mouse hearts. Furthermore, we found that the sequence of circRNAs can deviate from the sequence derived from the genome sequence, an important factor in assessing potential functions. Integration of additional data yielded evidence for m6A-modification of circRNAs, potentially linked to translation as well as circRNAs overlapping with potential Agonaut2 binding sites, indicating potential association with the RISC complex. Moreover, we describe, for the first time in cardiac model systems, a sub class of circRNAs containing the start codon of their primary transcript (AUG circRNAs) and observe an enrichment for m6A-modifications and ribosome association.
Link: https://doi.org/10.3390/cells9071616
New publication: CASC3 promotes transcriptome-wide activation of nonsense-mediated decay by the exon junction complex
Posted on July 2020 by Thiago Britto Borges
Another publication from our magnificent collaboration with the Gehring lab, from the Institute for Genetics - University of Cologne. CASC3 is a core component of the Exon Junction Complex (EJC), a protein complex that signals whether introns were successfully spliced out from the premature mRNA. Importantly, the EJC can signal aberrant translation when an EJC downstream to stop codon indicates the premature end of the translation. This aberrant protein products are likely truncated, and in the worst case harmful for the cell. In this manuscript, we show that cells that were genetically modified to remove CASC3 have a significant abundance increase in transcripts with premature termination codons. Many of these transcripts are shared with cells showing reduced non-sense mediated RNA decay activity (SMG6 / SMG7 mutants). In the absence of CASC3, EJC composition and EJC-dependent splicing are unchanged. We propose that CASC3 equips the EJC with the persisting ability to communicate with the NMD machinery in the cytoplasm. Collectively, our results characterize CASC3 as a peripheral EJC protein that tailors the transcriptome by promoting the degradation of EJC-dependent NMD substrates. Our work establishes and details the importance of CASC3 on the NMD process, which helps us to better understand the process of RNA degradation and its role in cardiac diseases.
Link: https://doi.org/10.1093/nar/gkaa564
New publication in Molecular Cell: An Insulin-Sensitive Circular RNA That Regulates Lifespan in Drosophila
Posted on June 2020 by Christoph Dieterich
Abstract
Circular RNAs (circRNAs) are abundant and accumulate with age in neurons of diverse species. However, only few circRNAs have been functionally characterized, and their role during aging has not been addressed. Here, we use transcriptome profiling during aging and find that accumulation of circRNAs is slowed down in long-lived insulin mutant flies. Next, we characterize the in vivo function of a circRNA generated by the sulfateless gene (circSfl), which is consistently upregulated, particularly in the brain and muscle, of diverse long-lived insulin mutants. Strikingly, lifespan extension of insulin mutants is dependent on circSfl, and overexpression of circSfl alone is sufficient to extend the lifespan. Moreover, circSfl is translated into a protein that shares the N terminus and potentially some functions with the full-length Sfl protein encoded by the host gene. Our study demonstrates that insulin signaling affects global circRNA accumulation and reveals an important role of circSfl during aging in vivo.
Link: https://pubmed.ncbi.nlm.nih.gov/32592682
Published: RNA Modification Level Estimation with pulseR
Posted on December 11, 2018 by Christoph Dieterich
Abstract
RNA modifications regulate the complex life of transcripts. An experimental approach called LAIC-seq was developed to characterize modification levels on a transcriptome-wide scale. In this method, the modified and unmodified molecules are separated using antibodies specific for a given RNA modification (e.g., m6A). In essence, the procedure of biochemical separation yields three fractions: Input, eluate, and supernatent, which are subjected to RNA-seq. In this work, we present a bioinformatics workflow, which starts from RNA-seq data to infer gene-specific modification levels by a statistical model on a transcriptome-wide scale. Our workflow centers around the pulseR package, which was originally developed for the analysis of metabolic labeling experiments. We demonstrate how to analyze data without external normalization (i.e., in the absence of spike-ins), given high efficiency of separation, and how, alternatively, scaling factors can be derived from unmodified spike-ins. Importantly, our workflow provides an estimate of uncertainty of modification levels in terms of confidence intervals for model parameters, such as gene expression and RNA modification levels. We also compare alternative model parametrizations, log-odds, or the proportion of the modified molecules and discuss the pros and cons of each representation. In summary, our workflow is a versatile approach to RNA modification level estimation, which is open to any read-count-based experimental approach.
https://www.mdpi.com/2073-4425/9/12/619
Posted in Publications
Dieterich Lab is now a member of epitran.eu
Posted on December 5, 2018 by Christoph Dieterich
We are now an official member of the Epitran network (check out: https://epitran.eu )
Posted in General
Posted on November 26, 2018 by Christoph Dieterich
Did you ever wonder how ncRNAs could influence behavior ?
Then, you would probably like to read on it in our new EMBO reports manuscript by
Lackinger, M., Sungur, A.Ö., Daswani, R., Soutschek, M., Bicker, S., Stemmler, L., Wüst, T., Fiore, R., Dieterich, C., Schwarting, R.K.W., Wöhr, M. and Schratt, G.
Aberrant synaptic function is thought to underlie social deficits in neurodevelopmental disorders such as autism and schizophrenia. microRNAs have been shown to regulate synapse development and plasticity, their potential involvement in the control of social behaviour in mammals however remains unexplored. Here we show that deletion of the large placental mammal-specific miR379-410 cluster in mice unexpectedly leads to hypersocial behaviour, which is accompanied by increased excitatory synaptic transmission and exaggerated expression of ionotropic glutamate receptor complexes in the hippocampus. Bioinformatics further allowed us to identify five “hub” microRNAs whose deletion accounts for a large part of the upregulation of excitatory synaptic genes, including Cnih2, Dlgap3, Prr7 and Src. Thus, miR379-410 is a natural brake for sociability and interfering with specific members of this cluster could represent a therapeutic strategy for social deficits in neurodevelopmental disorders.
Posted in General
CircTools manuscript accepted at Bioinformatics
Posted on November 16, 2018 by Christoph Dieterich
circtools: a modular, python-based framework for circRNA-related tools that unifies several functionalities in a single, command line driven software has been accepted for publication in Bioinformatics.
Please visit https://github.com/dieterich-lab/circtools for more information.
Posted in Publications, Software
Methods for Analysis of Circular RNAs: No Tautology
Posted on October 24, 2018 by Christoph Dieterich
We are excited to announce funding by EMBO for implementing a workshop on circular RNAs.
Organizers: Vladimir Benes (main), Irene Bozzoni, Marie-Laure Baudet and
Christoph Dieterich
Category: EMBO Practical Course
Title: EMBO Practical Course: Methods for analysis of circular RNAs: No tautology
Dates: 17 November 2019 – 22 November 2019
Location: DE–Heidelberg
https://www.embl.de/training/events/2019/CIR19-01/index.html
Posted in Conference, General
Advanced Training with Oxford Nanopore Technologies
Posted on October 17, 2018 by Christoph Dieterich
Join us for an advanced training experience using the Oxford Nanopore Technologies (ONT) platform. We will start with an introduction into ONT technology and devices, with the goal of covering end to end workflows for the preparation and analysis of human and yeast samples using whole genome and barcoded cDNA sequencing approaches. This course will cover the wet lab preparation of libraries from genomic DNA and total RNA, with a focus on the critical steps and potential pitfalls and understanding what constitutes a ‘good’ sample for purpose of best results using the technology. The training includes an overview of the MinKNOW GUI for GridION and MinION devices. We then cover methods available for basecalling and analysis of samples for structural variants and differential gene expression, using both Oxford Nanopore and open source tools.
More information and application at https://www.embl.de/training/events/2019/NAN19-01/index.html
Posted in Conference
Guardians of the transcriptome
Posted on October 11, 2018 by Christoph Dieterich
Our new article on “Exon junction complexes suppress spurious splice sites to safeguard transcriptome integrity” is in press and will appear in Molecular Cell beginning of November. Congratulations to the team of authors:
Volker Boehm1, Thiago Britto-Borges2,3, Anna-Lena Steckelberg1,4, Kusum K. Singh1,5, Jennifer V. Gerbracht1, Elif Gueney1, Lorea Blazquez6,7, Janine Altmüller8,9,10, Christoph Dieterich2,3, Niels H. Gehring1,11
Productive splicing of human pre-mRNAs requires the correct selection of authentic splice sites (SS) from the large pool of potential SS. Although SS consensus sequence and splicing regulatory proteins are known to influence SS usage, the mechanisms ensuring the effective suppression of cryptic SS are insufficiently explored. Here, we find that many aberrant exonic SS are efficiently silenced by the exon junction complex (EJC), a multi-protein complex that is deposited on spliced mRNA near the exon-exon junction. Upon depletion of EJC proteins, cryptic SS are de-repressed, leading to the mis-splicing of a broad set of mRNAs. Mechanistically, the EJC-mediated recruitment of the splicing regulator RNPS1 inhibits cryptic 5′SS usage, while the deposition of the EJC core directly masks reconstituted 3′SS, thereby precluding transcript disintegration. Thus, the EJC protects the transcriptome of mammalian cells from inadvertent loss of exonic sequences and safeguards the expression of intact, full length mRNAs.
Posted in General, Publications
DZHK PostDoc Start-up Grants awarded
Posted on March 1, 2018 by Anne Ammerstorfer
Congratulations to Tobias Jakobi, Heidelberg/Mannheim.
He received a PostDoc Start-up grant for:
“Investigating roles of dynamic RNA editing in the endoplasmic reticulum stress response in the heart”
Posted in General
Our book on circular RNAs is out (Springer Press)
Posted on January 15, 2018 by Anne Ammerstorfer
Circular RNAs (series: Methods in Molecular Biology) has been published.
Editor: Christoph Dieterich & Argyris Papantonis
Ein Paper, das unser neues Werkzeug zur Analyse von RNA-Sequenzen zur Markierung von RNA-Sequenzen beschreibt, ist jetzt online verfügbar!
Motivation:
Sequenziermaschinen mit hohem Durchsatz können viele Proben in einem einzigen Durchlauf verarbeiten. Für Illumina-Systeme werden Sequenz-Lesevorgänge mit einem zusätzlichen DNA-Tag versehen, das in den jeweiligen Sequenzierungsadaptern enthalten ist. Die Erkennung von Strichcode- und Adaptorsequenzen wird daher üblicherweise für die Analyse von Sequenzierungsdaten der nächsten Generation benötigt. Flexbar führt das Demultiplexen basierend auf Barcodes und Adapterabgleich für solche Daten durch. Weiterlesen...
Abstract: Synaptisches Downscaling ist ein homöostatischer Mechanismus, der es Neuronen erlaubt, die Feuerrate bei chronisch erhöhten Netzwerkaktivitäten zu reduzieren. Synaptisches Downscaling ist zwar wichtig für die Entwicklung von neuronalen Schaltkreisen und Epilepsie, die zugrundeliegenden Mechanismen sind jedoch kaum beschrieben. Wir führten kleine RNA-Profiling in Picrotoxin (PTX) behandelten Hippocampus-Neuronen, ein Modell der synaptischen Downscaling. Dabei identifizierten wir acht microRNAs (miRNAs), die als Reaktion auf PTX erhöht wurden, einschließlich miR-129-5p, deren Hemmung die synaptische Herabstufung in vitro blockierte und die Schwere der epileptischen Anfälle in vivo verringerte. Unter Verwendung von Transkriptom-, Proteom- und bioinformatischer Analyse identifizierten wir Calcium-Pumpe Atp2b4 und Doublecortin (Dcx) als miR-129-5p Ziele. Die Wiederherstellung der Atp2b4- und Dcx-Expression war ausreichend, um ein synaptisches Herunterskalieren in PTX-behandelten Neuronen zu verhindern. Darüber hinaus charakterisierten wir ein funktionelles Crosstalk zwischen miR-129-5p und dem RNA-bindenden Protein (RBP) Rbfox1. In Abwesenheit von PTX förderte Rbfox1 die Expression von Atp2b4 und Dcx. Bei der PTX-Behandlung wurde die Expression von Rbfox1 durch miR-129-5p herunterreguliert, wodurch Atp2b4 und Dcx unterdrückt werden konnten. Wir identifizierten daher ein neuartiges aktivitätsabhängiges miRNA / RBP-Crosstalk während der synaptischen Skalierung mit möglichen Implikationen für die Homöostase und Epileptogenese des Neuronalen Netzes.
Finden Sie mich auf Pubmed: www.ncbi.nlm.nih.gov/pubmed/28487411
Eine Woche wunderbare RNA modification Wissenschaft in Ventura / Kalifornien.
Wir haben eine weitere Publikation zur Identifizierung von translatierten RNA-Regionen aus Ribosom-Fußdruckdaten in Nucleic Acids Research.
Hier finden Sie alle weiteren Details: https://www.ncbi.nlm.nih.gov/pubmed/28126919
JACUSA: site-specific identification of RNA editing events from replicate sequencing data.
JACUSA: Site-specific identification of RNA editing events from replicate sequencing data
Noormohammadi A, Khodakarami A, Gutierrez-Garcia R, Lee HJ, Koyuncu S, König T, Schindler C, Saez I, Fatima A, Dieterich C, Vilchez D.
Nat Commun. 2016 Nov 28;7:13649. doi: 10.1038/ncomms13649.
PMID: 27892468
Reducing RBM20 activity improves diastolic dysfunction and cardiac atrophy.
Hinze F, Dieterich C, Radke MH, Granzier H, Gotthardt M.
J Mol Med (Berl). 2016 Nov 26. [Epub ahead of print]
PMID: 27889803
Wir begrüßen Ralf Hauenschild und Parisa Rezaee Borj in unserem Team!
Ivan Kel; Zisong Chang; Nadia Galluccio; Margherita Romeo; Stefano Beretta; Luisa Diomede; Alessandra Mezzelani; Luciano Milanesi; Christoph Dieterich; Ivan Merelli. SPIRE, a modular pipeline for eQTL analysis of RNA-Seq data, reveals a regulatory hotspot controlling miRNA expression in C. elegans
Wir heißen Amit Singh und Aleksei Uvarovskii in unserem Team willkommen.
Our software contribution
FUCHS – Towards full circular RNA characterization using RNAseq
has been selected for a talk at GCB2016
Le HQ, Ghatak S, Yeung CC, Tellkamp F,Günschmann C, Dieterich C, Yeroslaviz A, Habermann B, Pombo A, Niessen CM, Wickström SA.
Mechanical regulation of transcription controls Polycomb-mediated gene silencing during lineage commitment.
Unser Clusterserver ist angekommen und installiert.
Authoren: Shuhei Nakamura, Özlem Karalay, Philipp S. Jäger, MakotoHorikawa, Corinna Klein, Kayo Nakamura, Christian Latza, Sven E. Templer, Christoph Dieterich & Adam Antebi
Eine Zusammenarbeit mit unseren lieben Kollegen vom MPI-AGE wurde für die Publikation in Nature Communications akzeptiert.
Unser neuer Clusterserver ist bestellt und wir erwarten sehnsüchtig unser Weihnachtsgeschenk.
