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1.
Noncoding RNA Res. 2018 Feb 25;3(1):1-11. doi: 10.1016/j.ncrna.2018.02.002. eCollection 2018 Mar.

Circular RNAs in the cardiovascular system.

Author information

1
Cardiovascular Research Unit, Luxembourg Institute of Health, Luxembourg, Luxembourg.
2
Experimental Cardiology, Academic Medical Center, Amsterdam, The Netherlands.
3
German Center for Cardiovascular Research, University Hospital Heidelberg, Heidelberg, Germany.
4
Department of Intelligent Systems, Jozef Stefan Institute, Ljubljana, Slovenia.

Abstract

Until recently considered as rare, circular RNAs (circRNAs) are emerging as important regulators of gene expression. They are ubiquitously expressed and represent a novel branch of the family of non-coding RNAs. Recent investigations showed that circRNAs are regulated in the cardiovascular system and participate in its physiological and pathological development. In this review article, we will provide an overview of the role of circRNAs in cardiovascular health and disease. After a description of the biogenesis of circRNAs, we will summarize what is known of the expression, regulation and function of circRNAs in the cardiovascular system. We will then address some technical aspects of circRNAs research, discussing how artificial intelligence may aid in circRNAs research. Finally, the potential of circRNAs as biomarkers of cardiovascular disease will be addressed and directions for future research will be proposed.

KEYWORDS:

Artificial intelligence; Biomarker; CRISPR, clustered regularly interspaced short palindromic repeats; CV, cardiovascular; Cardiovascular disease; Cardiovascular system; Circular RNAs; DCM, dilated cardiomyopathy; EMT, epithelial-mesenchymal transition; Non-coding RNAs; RNA-seq, RNA sequencing; RPAD, RNase R treatment followed by polyadenylation and poly(A)+ RNA depletion; RT-qPCR, reverse transcription quantitative polymerase chain reaction; circRNAs, circular RNAs; lncRNAs, long non-coding RNAs; miRNAs, microRNAs; ncRNAs, non-coding RNAs

Publication type

Publication type

2.
Stud Health Technol Inform. 2018;253:165-169.

De-Identification of German Medical Admission Notes.

Author information

1
Department of Computational Linguistics, University of Heidelberg, Heidelberg, Germany.
2
Section of Bioinformatics and Systems Cardiology, Klaus Tschira Institute for Integrative Computational Cardiology and Department of Internal Medicine III, University Hospital Heidelberg, German Center for Cardiovascular Research (DZHK) - Partner site Heidelberg/Mannheim.

Abstract

Medical texts are a vast resource for medical and computational research. In contrast to newswire or wikipedia texts medical texts need to be de-identified before making them accessible to a wider NLP research community. We created a prototype for German medical text de-identification and named entity recognition using a three-step approach. First, we used well known rule-based models based on regular expressions and gazetteers, second we used a spelling variant detector based on Levenshtein distance, exploiting the fact that the medical texts contain semi-structured headers including sensible personal data, and third we trained a named entity recognition model on out of domain data to add statistical capabilities to our prototype. Using a baseline based on regular expressions and gazetteers we could improve F2-score from 78% to 85% for de-identification. Our prototype is a first step for further research on German medical text de-identification and could show that using spelling variant detection and out of domain trained statistical models can improve de-identification performance significantly.

KEYWORDS:

De-identification; anonymization; medical admission notes; named entity recognition; personal health information

PMID:
30147065
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3.
Methods Inf Med. 2018 Jul;57(S 01):e66-e81. doi: 10.3414/ME18-02-0002. Epub 2018 Jul 17.

HiGHmed - An Open Platform Approach to Enhance Care and Research across Institutional Boundaries.

Abstract

INTRODUCTION:

This article is part of the Focus Theme of Methods of Information in Medicine on the German Medical Informatics Initiative. HiGHmed brings together 24 partners from academia and industry, aiming at improvements in care provision, biomedical research and epidemiology. By establishing a shared information governance framework, data integration centers and an open platform architecture in cooperation with independent healthcare providers, the meaningful reuse of data will be facilitated. Complementary, HiGHmed integrates a total of seven Medical Informatics curricula to develop collaborative structures and processes to train medical informatics professionals, physicians and researchers in new forms of data analytics.

GOVERNANCE AND POLICIES:

We describe governance structures and policies that have proven effective during the conceptual phase. These were further adapted to take into account the specific needs of the development and networking phase, such as roll-out, carerelated aspects and our focus on curricula development in Medical Inform atics.

ARCHITECTURAL FRAMEWORK AND METHODOLOGY:

To address the challenges of organizational, technical and semantic interoperability, a concept for a scalable platform architecture, the HiGHmed Platform, was developed. We outline the basic principles and design goals of the open platform approach as well as the roles of standards and specifications such as IHE XDS, openEHR, SNOMED CT and HL7 FHIR. A shared governance framework provides the semantic artifacts which are needed to establish semantic interoperability.

USE CASES:

Three use cases in the fields of oncology, cardiology and infection control will demonstrate the capabilities of the HiGHmed approach. Each of the use cases entails diverse challenges in terms of data protection, privacy and security, including clinical use of genome sequencing data (oncology), continuous longitudinal monitoring of physical activity (cardiology) and cross-site analysis of patient movement data (infection control).

DISCUSSION:

Besides the need for a shared governance framework and a technical infrastructure, backing from clinical leaders is a crucial factor. Moreover, firm and sustainable commitment by participating organizations to collaborate in further development of their information system architectures is needed. Other challenges including topics such as data quality, privacy regulations, and patient consent will be addressed throughout the project.

PMID:
30016813
DOI:
10.3414/ME18-02-0002
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Conflict of interest statement

Disclosure The authors report no conflicts of interest in this work.

4.
Angew Chem Int Ed Engl. 2018 Jun 25;57(26):7893-7897. doi: 10.1002/anie.201713188. Epub 2018 Apr 27.

A Vastly Increased Chemical Variety of RNA Modifications Containing a Thioacetal Structure.

Author information

1
Institute of Pharmacy and Biochemistry, Johannes Gutenberg-University Mainz, Staudingerweg 5, 55128, Mainz, Germany.
2
Laboratoire de Chimie et Biologie des Métaux, Université Grenoble Alpes, CEA/BIG, CNRS, 17 rue des martyrs, 38000, Grenoble, France.
3
Next-Generation Sequencing Core Facility, FR3209 Bioingénierie Moléculaire Cellulaire et Thérapeutique, CNRS, Lorraine University, 54505, Vandoeuvre-les-Nancy, France.
4
Department II of Internal Medicine and Center for Molecular Medicine, University of Cologne, Kerpener Strasse 62, 50937, Cologne, Germany.
5
Institute of Molecular Biology (IMB), Ackermannweg 4, 55128, Mainz, Germany.
6
German Center for Cardiovascular Research (DZHK), University Hospital Heidelberg, Im Neuenheimer Feld 669, 69120, Heidelberg, Germany.
7
Laboratoire Ingénierie Moléculaire et Physiopathologie Articulaire (IMoPA) UMR7365 CNRS-UL, BioPôle de l'Université de Lorraine Campus Biologie-Santé, 9 avenue de la Forêt de Haye, CS 50184, 54505, Vandoeuvre-les-Nancy, France.

Abstract

Recently discovered new chemical entities in RNA modifications have involved surprising functional groups that enlarge the chemical space of RNA. Using LC-MS, we found over 100 signals of RNA constituents that contained a ribose moiety in tRNAs from E. coli. Feeding experiments with variegated stable isotope labeled compounds identified 37 compounds that are new structures of RNA modifications. One structure was elucidated by deuterium exchange and high-resolution mass spectrometry. The structure of msms2 i6 A (2-methylthiomethylenethio-N6-isopentenyl-adenosine) was confirmed by methione-D3 feeding experiments and by synthesis of the nucleobase. The msms2 i6 A contains a thioacetal, shown in vitro to be biosynthetically derived from ms2 i6 A by the radical-SAM enzyme MiaB. This enzyme performs thiomethylation, forming ms2 i6 A from i6 A in a first turnover. The new thioacetal is formed by a second turnover. Along with the pool of 36 new modifications, this work describes a new layer of RNA modification chemistry.

KEYWORDS:

LC-MS; RNA modifications; isotope labelling; radical-SAM enzymes; thioacetals

5.
Sci Rep. 2018 Mar 6;8(1):4092. doi: 10.1038/s41598-018-22384-9.

Insights into the ubiquitin-proteasome system of human embryonic stem cells.

Author information

1
Institute for Genetics and Cologne Excellence Cluster for Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Joseph-Stelzmann-Strasse 26, 50931, Cologne, Germany.
2
Department of Internal Medicine III and Klaus Tschira Institute for Computational Cardiology, Section of Bioinformatics and Systems Cardiology, Neuenheimer Feld 669, University Hospital, 69120, Heidelberg, Germany.
3
Institute for Genetics and Cologne Excellence Cluster for Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Joseph-Stelzmann-Strasse 26, 50931, Cologne, Germany. dvilchez@uni-koeln.de.

Abstract

Human embryonic stem cells (hESCs) exhibit high levels of proteasome activity, an intrinsic characteristic required for their self-renewal, pluripotency and differentiation. However, the mechanisms by which enhanced proteasome activity maintains hESC identity are only partially understood. Besides its essential role for the ability of hESCs to suppress misfolded protein aggregation, we hypothesize that enhanced proteasome activity could also be important to degrade endogenous regulatory factors. Since E3 ubiquitin ligases are responsible for substrate selection, we first define which E3 enzymes are increased in hESCs compared with their differentiated counterparts. Among them, we find HECT-domain E3 ligases such as HERC2 and UBE3A as well as several RING-domain E3s, including UBR7 and RNF181. Systematic characterization of their interactome suggests a link with hESC identity. Moreover, loss of distinct up-regulated E3s triggers significant changes at the transcriptome and proteome level of hESCs. However, these alterations do not dysregulate pluripotency markers and differentiation ability. On the contrary, global proteasome inhibition impairs diverse processes required for hESC identity, including protein synthesis, rRNA maturation, telomere maintenance and glycolytic metabolism. Thus, our data indicate that high proteasome activity is coupled with other determinant biological processes of hESC identity.

6.
Methods Mol Biol. 2018;1724:9-25. doi: 10.1007/978-1-4939-7562-4_2.

Deep Computational Circular RNA Analytics from RNA-seq Data.

Author information

1
Section of Bioinformatics and Systems Cardiology, Department of Internal Medicine III, Klaus Tschira Institute for Integrative Computational Cardiology, University Hospital Heidelberg, Heidelberg, Germany. tobias.jakobi@med.uni-heidelberg.de.
2
German Center for Cardiovascular Research (DZHK)-Partner site Heidelberg/Mannheim, Heidelberg, Germany. tobias.jakobi@med.uni-heidelberg.de.
3
Section of Bioinformatics and Systems Cardiology, Department of Internal Medicine III, Klaus Tschira Institute for Integrative Computational Cardiology, University Hospital Heidelberg, Heidelberg, Germany.
4
German Center for Cardiovascular Research (DZHK)-Partner site Heidelberg/Mannheim, Heidelberg, Germany.

Abstract

Circular RNAs (circRNAs) have been first described as "scrambled exons" in the 1990s. CircRNAs originate from back splicing or exon skipping of linear RNA templates and have continuously gained attention in recent years due to the availability of high-throughput whole-transcriptome sequencing methods. Numerous manuscripts describe thousands of circRNAs throughout uni- and multicellular eukaryote species and demonstrated that they are conserved, stable, and abundant in specific tissues or conditions. This manuscript provides a walk-through of our bioinformatics toolbox, which covers all aspects of in silico circRNA analysis, starting from raw sequencing data and back-splicing junction discovery to circRNA quantitation and reconstruction of internal the circRNA structure.

KEYWORDS:

Bioinformatics; Circular; Circular RNA detection; RNA analysis; Whole-transcriptome sequencing

7.
Nat Commun. 2017 Nov 13;8(1):1456. doi: 10.1038/s41467-017-01744-5.

A post-transcriptional program coordinated by CSDE1 prevents intrinsic neural differentiation of human embryonic stem cells.

Author information

1
Cologne Excellence Cluster for Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Joseph Stelzmann Strasse 26, 50931, Cologne, Germany.
2
Laboratory for Developmental and Regenerative RNA biology, Center for Molecular Medicine Cologne (CMMC), University of Cologne, Robert-Koch-Str. 21, 50931, Cologne, Germany.
3
Department of Dermatology and Venereology, University Hospital of Cologne, Joseph Stelzmann Strasse 26, 50931, Cologne, Germany.
4
Gene Regulation, Stem Cells and Cancer Programme, Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, 08003, Barcelona, Spain.
5
Centro de Investigación Genética y Genómica, Facultad de Ciencias de la Salud Eugenio Espejo, Universidad Tecnologica Equinoccial, Avenue Mariscal Sucre, 170129, Quito, Ecuador.
6
Department of Chemical Physiology, 10550 North Torrey Pines Road, SR111, The Scripps Research Institute, La Jolla, CA, 92037, USA.
7
Section of Bioinformatics and Systems Cardiology, Department of Internal Medicine III and Klaus Tschira Institute for Computational Cardiology, Neuenheimer Feld 669, University Hospital, 69120, Heidelberg, Germany.
8
Cologne Excellence Cluster for Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Joseph Stelzmann Strasse 26, 50931, Cologne, Germany. dvilchez@uni-koeln.de.

Abstract

While the transcriptional network of human embryonic stem cells (hESCs) has been extensively studied, relatively little is known about how post-transcriptional modulations determine hESC function. RNA-binding proteins play central roles in RNA regulation, including translation and turnover. Here we show that the RNA-binding protein CSDE1 (cold shock domain containing E1) is highly expressed in hESCs to maintain their undifferentiated state and prevent default neural fate. Notably, loss of CSDE1 accelerates neural differentiation and potentiates neurogenesis. Conversely, ectopic expression of CSDE1 impairs neural differentiation. We find that CSDE1 post-transcriptionally modulates core components of multiple regulatory nodes of hESC identity, neuroectoderm commitment and neurogenesis. Among these key pro-neural/neuronal factors, CSDE1 binds fatty acid binding protein 7 (FABP7) and vimentin (VIM) mRNAs, as well as transcripts involved in neuron projection development regulating their stability and translation. Thus, our results uncover CSDE1 as a central post-transcriptional regulator of hESC identity and neurogenesis.

PMID:
29129916
PMCID:
PMC5682285
DOI:
10.1038/s41467-017-01744-5
[Indexed for MEDLINE]
Free PMC Article
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8.
Eur Heart J. 2017 Dec 7;38(46):3449-3460. doi: 10.1093/eurheartj/ehx545.

Clinical genetics and outcome of left ventricular non-compaction cardiomyopathy.

Author information

1
Department of Medicine III, Institute for Cardiomyopathies Heidelberg (ICH), University of Heidelberg, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany.
2
DZHK (German Centre for Cardiovascular Research), Heidelberg, Germany.
3
Department of Cardiology, Institute of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430022 Wuhan, China.
4
Experimental and Clinical Research Center (ECRC), A Joint Cooperation of Charité Medical Faculty and Max Delbrück Center for Molecular Medicine (MDC), Augustenburger Platz 1, 13353 Berlin, Germany.
5
DZHK (German Centre for Cardiovascular Research), Berlin, Germany.
6
Neuromuscular and Cardiovascular Cell Biology, Max Delbrück Center for Molecular Medicine, Robert-Rössle-Str. 10, 13092 Berlin, Germany.
7
Department of Human Genetics, University of Heidelberg, Im Neuenheimer Feld 366, 69120 Heidelberg, Germany.
8
Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430022 Wuhan, China.
9
Department of Ultrasound, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430022 Wuhan, China.
10
Department of Cardiology, Virchow Klinikum, Charité University Medicine Berlin, Augustenburger Platz 1, 13353 Berlin, Germany.
11
Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
12
Department of Bioinformatics, University of Saarland, Building E2.1, 66123 Saarbrücken, Germany.
13
Department of Medicine III, Klaus Tschira Institute for Computational Cardiology, University of Heidelberg, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany.
14
Department of Cardiology and Pneumology, Georg-August-University Göttingen, Robert-Koch-Str. 40, 37075 Göttingen, Germany.
15
DZHK (German Centre for Cardiovascular Research), Göttingen, Germany.

Abstract

Aims:

In this study, we aimed to clinically and genetically characterize LVNC patients and investigate the prevalence of variants in known and novel LVNC disease genes.

Introduction:

Left ventricular non-compaction cardiomyopathy (LVNC) is an increasingly recognized cause of heart failure, arrhythmia, thromboembolism, and sudden cardiac death. We sought here to dissect its genetic causes, phenotypic presentation and outcome.

Methods and results:

In our registry with follow-up of in the median 61 months, we analysed 95 LVNC patients (68 unrelated index patients and 27 affected relatives; definite familial LVNC = 23.5%) by cardiac phenotyping, molecular biomarkers and exome sequencing. Cardiovascular events were significantly more frequent in LVNC patients compared with an age-matched group of patients with non-ischaemic dilated cardiomyopathy (hazard ratio = 2.481, P = 0.002). Stringent genetic classification according to ACMG guidelines revealed that TTN, LMNA, and MYBPC3 are the most prevalent disease genes (13 patients are carrying a pathogenic truncating TTN variant, odds ratio = 40.7, Confidence interval = 21.6-76.6, P < 0.0001, percent spliced in 76-100%). We also identified novel candidate genes for LVNC. For RBM20, we were able to perform detailed familial, molecular and functional studies. We show that the novel variant p.R634L in the RS domain of RBM20 co-segregates with LVNC, leading to titin mis-splicing as revealed by RNA sequencing of heart tissue in mutation carriers, protein analysis, and functional splice-reporter assays.

Conclusion:

Our data demonstrate that the clinical course of symptomatic LVNC can be severe. The identified pathogenic variants and distribution of disease genes-a titin-related pathomechanism is found in every fourth patient-should be considered in genetic counselling of patients. Pathogenic variants in the nuclear proteins Lamin A/C and RBM20 were associated with worse outcome.

KEYWORDS:

Next-generation whole-Exome sequencing; Non-compaction cardiomyopathy; RBM20; Titin

PMID:
29029073
DOI:
10.1093/eurheartj/ehx545
[Indexed for MEDLINE]
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9.
Bioinformatics. 2017 Oct 15;33(20):3305-3307. doi: 10.1093/bioinformatics/btx368.

pulseR: Versatile computational analysis of RNA turnover from metabolic labeling experiments.

Author information

1
Section of Bioinformatics and Systems Cardiology, Department of Internal Medicine III, Klaus Tschira Institute for Integrative Computational Cardiology, University Hospital Heidelberg.
2
German Center for Cardiovascular Research (DZHK) - Partner site Heidelberg/Mannheim, 69120 Heidelberg, Germany.

Abstract

Motivation:

Metabolic labelling of RNA is a well-established and powerful method to estimate RNA synthesis and decay rates. The pulseR R package simplifies the analysis of RNA-seq count data that emerge from corresponding pulse-chase experiments.

Results:

The pulseR package provides a flexible interface and readily accommodates numerous different experimental designs. To our knowledge, it is the first publicly available software solution that models count data with the more appropriate negative-binomial model. Moreover, pulseR handles labelled and unlabelled spike-in sets in its workflow and accounts for potential labeling biases (e.g. number of uridine residues).

Availability and implementation:

The pulseR package is freely available at https://github.com/dieterich-lab/pulseR under the GPLv3.0 licence.

Contact:

a.uvarovskii@uni-heidelberg.de or christoph.dieterich@uni-heidelberg.de.

Supplementary information:

Supplementary data are available at Bioinformatics online.

PMID:
29028260
DOI:
10.1093/bioinformatics/btx368
[Indexed for MEDLINE]
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10.
PLoS One. 2017 Sep 25;12(9):e0185376. doi: 10.1371/journal.pone.0185376. eCollection 2017.

Cellular heterogeneity contributes to subtype-specific expression of ZEB1 in human glioblastoma.

Author information

1
Dept. of Neurology, Charité -Universitätsmedizin Berlin, Berlin, Germany.
2
Dept. of Experimental Neurology, Charité -Universitätsmedizin Berlin, Berlin, Germany.
3
Berlin Institute of Health (BIH), Berlin, Germany.
4
Dept. of Neuropathology, Charité -Universitätsmedizin Berlin, Berlin, Germany.
5
German Cancer Consortium (DKTK), Partner Site Charité Berlin, Berlin, Berlin, Germany.
6
Center for Stroke Research Berlin, Charité -Universitätsmedizin Berlin, Berlin, Germany.
7
Dept. for Biostatistics and Clinical Epidemiology, Charité -Universitätsmedizin Berlin, Berlin, Germany.
8
Dept. of Pathology, Charité -Universitätsmedizin Berlin, Berlin, Germany.
9
Dept. of Neurosurgery, Charité -Universitätsmedizin Berlin, Berlin, Germany.
10
Computational RNA Biology and Ageing Group, Max-Planck-Institute for the Biology of Ageing, Cologne, Germany.
11
Dept. of Biomedicine, University of Bergen, Bergen, Norway.
12
Department of Pathology, Haukeland University Hospital, Bergen, Norway.
13
Deutsches Zentrum für Herz-Kreislauf-Forschung (DZHK), Standort Berlin, Berlin, Germany.
14
Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE), Standort Berlin, Berlin, Germany.

Abstract

The transcription factor ZEB1 has gained attention in tumor biology of epithelial cancers because of its function in epithelial-mesenchymal transition, DNA repair, stem cell biology and tumor-induced immunosuppression, but its role in gliomas with respect to invasion and prognostic value is controversial. We characterized ZEB1 expression at single cell level in 266 primary brain tumors and present a comprehensive dataset of high grade gliomas with Ki67, p53, IDH1, and EGFR immunohistochemistry, as well as EGFR FISH. ZEB1 protein expression in glioma stem cell lines was compared to their parental tumors with respect to gene expression subtypes based on RNA-seq transcriptomic profiles. ZEB1 is widely expressed in glial tumors, but in a highly variable fraction of cells. In glioblastoma, ZEB1 labeling index is higher in tumors with EGFR amplification or IDH1 mutation. Co-labeling studies showed that tumor cells and reactive astroglia, but not immune cells contribute to the ZEB1 positive population. In contrast, glioma cell lines constitutively express ZEB1 irrespective of gene expression subtype. In conclusion, our data indicate that immune infiltration likely contributes to differential labelling of ZEB1 and confounds interpretation of bulk ZEB1 expression data.

PMID:
28945795
PMCID:
PMC5612763
DOI:
10.1371/journal.pone.0185376
[Indexed for MEDLINE]
Free PMC Article
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11.
Mol Syst Biol. 2017 Sep 15;13(9):939. doi: 10.15252/msb.20177663.

A proteomic atlas of insulin signalling reveals tissue-specific mechanisms of longevity assurance.

Author information

1
Max-Planck Institute for Biology of Ageing, Cologne, Germany.
2
CECAD Cologne Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases, Cologne, Germany.
3
Department of Proteomics and Signal Transduction, Max-Planck-Institute of Biochemistry, Martinsried, Germany.
4
Section of Bioinformatics and Systems Cardiology, Department of Internal Medicine III and Klaus Tschira Institute for Integrative Computational Cardiology, University of Heidelberg, Heidelberg, Germany.
5
DZHK (German Centre for Cardiovascular Research), Partner site Heidelberg/Mannheim, Heidelberg, Germany.
6
Institute of Healthy Ageing, and GEE, UCL, London, UK.
7
CECAD Cologne Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases, Cologne, Germany andreas.beyer@uni-koeln.de partridge@age.mpg.de.
8
Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany.
9
Max-Planck Institute for Biology of Ageing, Cologne, Germany andreas.beyer@uni-koeln.de partridge@age.mpg.de.

Abstract

Lowered activity of the insulin/IGF signalling (IIS) network can ameliorate the effects of ageing in laboratory animals and, possibly, humans. Although transcriptome remodelling in long-lived IIS mutants has been extensively documented, the causal mechanisms contributing to extended lifespan, particularly in specific tissues, remain unclear. We have characterized the proteomes of four key insulin-sensitive tissues in a long-lived Drosophila IIS mutant and control, and detected 44% of the predicted proteome (6,085 proteins). Expression of ribosome-associated proteins in the fat body was reduced in the mutant, with a corresponding, tissue-specific reduction in translation. Expression of mitochondrial electron transport chain proteins in fat body was increased, leading to increased respiration, which was necessary for IIS-mediated lifespan extension, and alone sufficient to mediate it. Proteasomal subunits showed altered expression in IIS mutant gut, and gut-specific over-expression of the RPN6 proteasomal subunit, was sufficient to increase proteasomal activity and extend lifespan, whilst inhibition of proteasome activity abolished IIS-mediated longevity. Our study thus uncovered strikingly tissue-specific responses of cellular processes to lowered IIS acting in concert to ameliorate ageing.

KEYWORDS:

ageing; insulin/IGF; mitochondria; proteasome; proteome

PMID:
28916541
PMCID:
PMC5615923
[Indexed for MEDLINE]
Free PMC Article
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12.
BMC Genomics. 2017 Sep 5;18(1):686. doi: 10.1186/s12864-017-4095-6.

Dual RNA-seq reveals no plastic transcriptional response of the coccidian parasite Eimeria falciformis to host immune defenses.

Author information

1
Institute of Biology, Molecular Parasitology, Humboldt-Universität zu Berlin, Philippstr. 13, Haus 14, 10115, Berlin, Germany.
2
FG16 - Mycotic and parasitic agents and mycobacteria, Robert Koch Institute, Berlin, Germany.
3
University Hospital Heidelberg - German Center for Cardiovascular Research (DZHK), Analysezentrum III, Im Neuenheimer Feld 669, 69120, Heidelberg, Germany.
4
Institute of Biology, Molecular Parasitology, Humboldt-Universität zu Berlin, Philippstr. 13, Haus 14, 10115, Berlin, Germany. emanuel.heitlinger@hu-berlin.de.
5
Leibniz Institute for Zoo and Wildlife Research, Research Group Ecology and Evolution of Parasite Host Interactions, Alfred-Kowalke-Str. 17, 10315, Berlin, Germany. emanuel.heitlinger@hu-berlin.de.

Abstract

BACKGROUND:

Parasites can either respond to differences in immune defenses that exist between individual hosts plastically or, alternatively, follow a genetically canalized ("hard wired") program of infection. Assuming that large-scale functional plasticity would be discernible in the parasite transcriptome we have performed a dual RNA-seq study of the lifecycle of Eimeria falciformis using infected mice with different immune status as models for coccidian infections.

RESULTS:

We compared parasite and host transcriptomes (dual transcriptome) between naïve and challenge infected mice, as well as between immune competent and immune deficient ones. Mice with different immune competence show transcriptional differences as well as differences in parasite reproduction (oocyst shedding). Broad gene categories represented by differently abundant host genes indicate enrichments for immune reaction and tissue repair functions. More specifically, TGF-beta, EGF, TNF and IL-1 and IL-6 are examples of functional annotations represented differently depending on host immune status. Much in contrast, parasite transcriptomes were neither different between Coccidia isolated from immune competent and immune deficient mice, nor between those harvested from naïve and challenge infected mice. Instead, parasite transcriptomes have distinct profiles early and late in infection, characterized largely by biosynthesis or motility associated functional gene groups, respectively. Extracellular sporozoite and oocyst stages showed distinct transcriptional profiles and sporozoite transcriptomes were found enriched for species specific genes and likely pathogenicity factors.

CONCLUSION:

We propose that the niche and host-specific parasite E. falciformis uses a genetically canalized program of infection. This program is likely fixed in an evolutionary process rather than employing phenotypic plasticity to interact with its host. This in turn might limit the potential of the parasite to adapt to new host species or niches, forcing it to coevolve with its host.

KEYWORDS:

Apicomplexa; Coccidia; Dual RNA-seq; Dual transcriptomics; Parasite lifecycle; Phenotypic plasticity; Transcriptional plasticity

PMID:
28870168
PMCID:
PMC5584376
DOI:
10.1186/s12864-017-4095-6
[Indexed for MEDLINE]
Free PMC Article
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13.
EMBO Mol Med. 2017 Sep;9(9):1279-1293. doi: 10.15252/emmm.201707565.

The cardiac microenvironment uses non-canonical WNT signaling to activate monocytes after myocardial infarction.

Author information

1
Department of Medicine III, University of Heidelberg, Heidelberg, Germany.
2
DZHK (German Centre for Cardiovascular Research), Partnersite, Heidelberg/Mannheim, Germany.
3
Institute of Pathology, University of Heidelberg, Heidelberg, Germany.
4
Tissue Bank of the National Center for Tumor Diseases (NCT), Heidelberg, Germany.
5
Division Signaling and Functional Genomics, German Cancer Research Center (DKFZ) and Heidelberg University, Heidelberg, Germany.
6
Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
7
Department of Medicine III, University of Heidelberg, Heidelberg, Germany florian.leuschner@med.uni-heidelberg.de.

Abstract

A disturbed inflammatory response following myocardial infarction (MI) is associated with poor prognosis and increased tissue damage. Monocytes are key players in healing after MI, but little is known about the role of the cardiac niche in monocyte activation. This study investigated microenvironment-dependent changes in inflammatory monocytes after MI RNA sequencing analysis of murine Ly6Chigh monocytes on day 3 after MI revealed differential regulation depending on location. Notably, the local environment strongly impacted components of the WNT signaling cascade. Analysis of WNT modulators revealed a strong upregulation of WNT Inhibitory Factor 1 (WIF1) in cardiomyocytes-but not fibroblasts or endothelial cells-upon hypoxia. Compared to wild-type (WT) littermates, WIF1 knockout mice showed severe adverse remodeling marked by increased scar size and reduced ejection fraction 4 weeks after MI While FACS analysis on day 1 after MI revealed no differences in neutrophil numbers, the hearts of WIF1 knockouts contained significantly more inflammatory monocytes than hearts from WT animals. Next, we induced AAV-mediated cardiomyocyte-specific WIF1 overexpression, which attenuated the monocyte response and improved cardiac function after MI, as compared to control-AAV-treated animals. Finally, WIF1 overexpression in isolated cardiomyocytes limited the activation of non-canonical WNT signaling and led to reduced IL-1β and IL-6 expression in monocytes/macrophages. Taken together, we investigated the cardiac microenvironment's interaction with recruited monocytes after MI and identified a novel mechanism of monocyte activation. The local initiation of non-canonical WNT signaling shifts the accumulating myeloid cells toward a pro-inflammatory state and impacts healing after myocardial infarction.

KEYWORDS:

inflammation; monocytes; myocardial infarction

PMID:
28774883
PMCID:
PMC5582413
DOI:
10.15252/emmm.201707565
[Indexed for MEDLINE]
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14.
Bioinformatics. 2017 Sep 15;33(18):2941-2942. doi: 10.1093/bioinformatics/btx330.

Flexbar 3.0 - SIMD and multicore parallelization.

Author information

1
Institute of Bioinformatics, Department of Mathematics and Computer Science, FU Berlin, 14195 Berlin, Germany.
2
Klaus Tschira Institute for Integrative Computational Cardiology, Department of Internal Medicine III, University of Heidelberg, 69120 Heidelberg, Germany.

Abstract

Motivation:

High-throughput sequencing machines can process many samples in a single run. For Illumina systems, sequencing reads are barcoded with an additional DNA tag that is contained in the respective sequencing adapters. The recognition of barcode and adapter sequences is hence commonly needed for the analysis of next-generation sequencing data. Flexbar performs demultiplexing based on barcodes and adapter trimming for such data. The massive amounts of data generated on modern sequencing machines demand that this preprocessing is done as efficiently as possible.

Results:

We present Flexbar 3.0, the successor of the popular program Flexbar. It employs now twofold parallelism: multi-threading and additionally SIMD vectorization. Both types of parallelism are used to speed-up the computation of pair-wise sequence alignments, which are used for the detection of barcodes and adapters. Furthermore, new features were included to cover a wide range of applications. We evaluated the performance of Flexbar based on a simulated sequencing dataset. Our program outcompetes other tools in terms of speed and is among the best tools in the presented quality benchmark.

Availability and implementation:

https://github.com/seqan/flexbar.

Contact:

johannes.roehr@fu-berlin.de or knut.reinert@fu-berlin.de.

PMID:
28541403
DOI:
10.1093/bioinformatics/btx330
[Indexed for MEDLINE]
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15.
EMBO J. 2017 Jun 14;36(12):1770-1787. doi: 10.15252/embj.201695748. Epub 2017 May 9.

A microRNA-129-5p/Rbfox crosstalk coordinates homeostatic downscaling of excitatory synapses.

Author information

1
Biochemisch-Pharmakologisches Centrum, Institut für Physiologische Chemie, Philipps-Universität Marburg, Marburg, Germany.
2
Section of Bioinformatics and Systems Cardiology, Klaus Tschira Institute for Integrative Computational Cardiology, Department of Internal Medicine III, German Center for Cardiovascular Research (DZHK), University Hospital Heidelberg, Heidelberg, Germany.
3
Physiology & Medical Physics Department, Royal College of Surgeons in Ireland, Dublin, Ireland.
4
Beaumont Hospital, Dublin, Ireland.
5
Epilepsiezentrum Frankfurt Rhein-Main, Neurozentrum, Goethe-Universität Frankfurt, Frankfurt, Germany.
6
Epilepsiezentrum Hessen - Marburg, Philipps-Universität Marburg, Marburg, Germany.
7
Department of Molecular Biology and Genetics and Interdisciplinary Nanoscience Center, Aarhus University, Aarhus, Denmark.
8
Institute for Genetics, University of Cologne, Cologne, Germany.
9
Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany.
10
Center for Molecular Medicine (CMMC), University of Cologne, Cologne, Germany.
11
Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany.
12
Biochemisch-Pharmakologisches Centrum, Institut für Physiologische Chemie, Philipps-Universität Marburg, Marburg, Germany schratt@staff.uni-marburg.de.

Abstract

Synaptic downscaling is a homeostatic mechanism that allows neurons to reduce firing rates during chronically elevated network activity. Although synaptic downscaling is important in neural circuit development and epilepsy, the underlying mechanisms are poorly described. We performed small RNA profiling in picrotoxin (PTX)-treated hippocampal neurons, a model of synaptic downscaling. Thereby, we identified eight microRNAs (miRNAs) that were increased in response to PTX, including miR-129-5p, whose inhibition blocked synaptic downscaling in vitro and reduced epileptic seizure severity in vivo Using transcriptome, proteome, and bioinformatic analysis, we identified the calcium pump Atp2b4 and doublecortin (Dcx) as miR-129-5p targets. Restoring Atp2b4 and Dcx expression was sufficient to prevent synaptic downscaling in PTX-treated neurons. Furthermore, we characterized a functional crosstalk between miR-129-5p and the RNA-binding protein (RBP) Rbfox1. In the absence of PTX, Rbfox1 promoted the expression of Atp2b4 and Dcx. Upon PTX treatment, Rbfox1 expression was downregulated by miR-129-5p, thereby allowing the repression of Atp2b4 and Dcx. We therefore identified a novel activity-dependent miRNA/RBP crosstalk during synaptic scaling, with potential implications for neural network homeostasis and epileptogenesis.

KEYWORDS:

RNA‐binding protein; epilepsy; homeostatic plasticity; microRNA; synaptic scaling

PMID:
28487411
PMCID:
PMC5470041
DOI:
10.15252/embj.201695748
[Indexed for MEDLINE]
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16.
Mol Cancer Res. 2017 May;15(5):532-540. doi: 10.1158/1541-7786.MCR-16-0322. Epub 2017 Feb 1.

Prognostic Relevance of Tumor Purity and Interaction with MGMT Methylation in Glioblastoma.

Author information

1
Department of Experimental Neurology, Charité - Universitätsmedizin Berlin, Berlin, Germany.
2
Department of Neuropathology, Charité - Universitätsmedizin Berlin, Berlin, Germany.
3
German Consortium for Translational Cancer Research (DKTK), Heidelberg, Germany.
4
Berlin Institute of Health (BIH), Berlin, Germany.
5
Department of Genomic Medicine, University of Texas MD Anderson Cancer Center, Houston, Texas.
6
Department of Neurosurgery, Charité - Universitätsmedizin Berlin, Berlin, Germany.
7
Computational RNA Biology and Ageing Group, Max-Planck-Institute for the Biology of Ageing, Cologne, Germany.
8
Department of Bioinformatics and Computational Biology, University of Texas MD Anderson Cancer Center, Houston, Texas.
9
Department of Experimental Neurology, Charité - Universitätsmedizin Berlin, Berlin, Germany. philipp.euskirchen@charite.de christoph.harms@charite.de.
10
Center for Stroke Research Berlin, Charité - Universitätsmedizin Berlin, Berlin, Germany.
11
Department of Neurology, Charité - Universitätsmedizin Berlin, Berlin, Germany.

Abstract

Promoter methylation status of O-6-methylguanine-DNA methyltransferase (MGMT), a DNA repair enzyme, is a critical biomarker in glioblastoma (GBM), as treatment decisions and clinical trial inclusion rely on its accurate assessment. However, interpretation of results is complicated by poor interassay reproducibility as well as a weak correlation between methylation status and expression levels of MGMT. This study systematically investigates the influence of tumor purity on tissue subjected to MGMT analysis. A quantitative, allele-specific real-time PCR (qAS-PCR) assay was developed to determine genotype and mutant allele frequency of telomerase promoter (pTERT) mutations as a direct measure of tumor purity. We studied tumor purity, pTERT mutation by Sanger sequencing, MGMT methylation by pyrosequencing, IDH1 mutation status, and clinical parameters in a cohort of high-grade gliomas (n = 97). The qAS-PCR reliably predicted pTERT genotype and tumor purity compared with independent methods. Tumor purity positively and significantly correlated with the extent of methylation in MGMT methylated GBMs. Extent of MGMT methylation differed significantly with respect to pTERT mutation hotspot (C228T vs. C250T). Interestingly, frontal lobe tumors showed greater tumor purity than those in other locations. Above all, tumor purity was identified as an independent prognostic factor in GBM. In conclusion, we determined mutual associations of tumor purity with MGMT methylation and pTERT mutations and found that the extent of MGMT methylation reflects tumor purity. In turn, tumor purity is prognostic in IDH1 wild-type GBM.Implications: Tumor purity is an independent prognostic marker in glioblastoma and is associated with the extent of MGMT methylation. Mol Cancer Res; 15(5); 532-40. ©2017 AACR.

PMID:
28148826
DOI:
10.1158/1541-7786.MCR-16-0322
[Indexed for MEDLINE]
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17.
Nucleic Acids Res. 2017 Apr 7;45(6):2960-2972. doi: 10.1093/nar/gkw1350.

Bayesian prediction of RNA translation from ribosome profiling.

Author information

1
Section of Bioinformatics and Systems Cardiology, Department of Internal Medicine III and Klaus Tschira Institute for Integrative Computational Cardiology, University of Heidelberg, 69120 Heidelberg, Germany.
2
DZHK (German Centre for Cardiovascular Research), Partner site Heidelberg/Mannheim, 69120 Heidelberg, Germany.
3
Max Plank Institute for the Biology of Ageing, 50931 Köln, Germany.
4
Friedrich Miescher Institute for Biomedical Research, 4058 Basel, Switzerland.
5
Faculty of Science, University of Basel, 4056 Basel, Switzerland.

Abstract

Ribosome profiling via high-throughput sequencing (ribo-seq) is a promising new technique for characterizing the occupancy of ribosomes on messenger RNA (mRNA) at base-pair resolution. The ribosome is responsible for translating mRNA into proteins, so information about its occupancy offers a detailed view of ribosome density and position which could be used to discover new translated open reading frames (ORFs), among other things. In this work, we propose Rp-Bp, an unsupervised Bayesian approach to predict translated ORFs from ribosome profiles. We use state-of-the-art Markov chain Monte Carlo techniques to estimate posterior distributions of the likelihood of translation of each ORF. Hence, an important feature of Rp-Bp is its ability to incorporate and propagate uncertainty in the prediction process. A second novel contribution is automatic Bayesian selection of read lengths and ribosome P-site offsets (BPPS). We empirically demonstrate that our read length selection technique modestly improves sensitivity by identifying more canonical and non-canonical ORFs. Proteomics- and quantitative translation initiation sequencing-based validation verifies the high quality of all of the predictions. Experimental comparison shows that Rp-Bp results in more peptide identifications and proteomics-validated ORF predictions compared to another recent tool for translation prediction.

PMID:
28126919
PMCID:
PMC5389577
DOI:
10.1093/nar/gkw1350
[Indexed for MEDLINE]
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18.
BMC Bioinformatics. 2017 Jan 3;18(1):7. doi: 10.1186/s12859-016-1432-8.

JACUSA: site-specific identification of RNA editing events from replicate sequencing data.

Author information

1
Max Planck Institute for Biology of Ageing, Joseph-Stelzmann Str. 9b, Cologne, 50931, Germany.
2
Berlin Institute for Medical Systems Biology, Max-Delbrück-Center for Molecular Medicine, Robert-Rössle-Strasse 10, Berlin, 13125, Germany.
3
Section of Bioinformatics and Systems Cardiology, Klaus Tschira Institute for Integrative Computational Cardiology at the Department of Internal Medicine III, University Hospital Heidelberg, Im Neuenheimer Feld 669, Heidelberg, 69120, Germany. christoph.dieterich@uni-heidelberg.de.
4
German Center for Cardiovascular Research (DZHK) - Partner site Heidelberg/Mannheim, Im Neuenheimer Feld 669, Heidelberg, 69120, Germany. christoph.dieterich@uni-heidelberg.de.

Abstract

BACKGROUND:

RNA editing is a co-transcriptional modification that increases the molecular diversity, alters secondary structure and protein coding sequences by changing the sequence of transcripts. The most common RNA editing modification is the single base substitution (A→I) that is catalyzed by the members of the Adenosine deaminases that act on RNA (ADAR) family. Typically, editing sites are identified as RNA-DNA-differences (RDDs) in a comparison of genome and transcriptome data from next-generation sequencing experiments. However, a method for robust detection of site-specific editing events from replicate RNA-seq data has not been published so far. Even more surprising, condition-specific editing events, which would show up as differences in RNA-RNA comparisons (RRDs) and depend on particular cellular states, are rarely discussed in the literature.

RESULTS:

We present JACUSA, a versatile one-stop solution to detect single nucleotide variant positions from comparing RNA-DNA and/or RNA-RNA sequencing samples. The performance of JACUSA has been carefully evaluated and compared to other variant callers in an in silico benchmark. JACUSA outperforms other algorithms in terms of the F measure, which combines precision and recall, in all benchmark scenarios. This performance margin is highest for the RNA-RNA comparison scenario. We further validated JACUSA's performance by testing its ability to detect A→I events using sequencing data from a human cell culture experiment and publicly available RNA-seq data from Drosophila melanogaster heads. To this end, we performed whole genome and RNA sequencing of HEK-293 cells on samples with lowered activity of candidate RNA editing enzymes. JACUSA has a higher recall and comparable precision for detecting true editing sites in RDD comparisons of HEK-293 data. Intriguingly, JACUSA captures most A→I events from RRD comparisons of RNA sequencing data derived from Drosophila and HEK-293 data sets.

CONCLUSION:

Our software JACUSA detects single nucleotide variants by comparing data from next-generation sequencing experiments (RNA-DNA or RNA-RNA). In practice, JACUSA shows higher recall and comparable precision in detecting A→I sites from RNA-DNA comparisons, while showing higher precision and recall in RNA-RNA comparisons.

KEYWORDS:

ADAR; APOBEC3; RNA editing; SNV; Variant calling

PMID:
28049429
PMCID:
PMC5210316
DOI:
10.1186/s12859-016-1432-8
[Indexed for MEDLINE]
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19.
Nat Commun. 2016 Nov 28;7:13649. doi: 10.1038/ncomms13649.

Somatic increase of CCT8 mimics proteostasis of human pluripotent stem cells and extends C. elegans lifespan.

Author information

1
Cologne Excellence Cluster for Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Joseph Stelzmann Strasse 26, Cologne 50931, Germany.
2
Section of Bioinformatics and Systems Cardiology, Department of Internal Medicine III and Klaus Tschira Institute for Computational Cardiology, Neuenheimer Feld 669, University Hospital, Heidelberg 69120, Germany.

Abstract

Human embryonic stem cells can replicate indefinitely while maintaining their undifferentiated state and, therefore, are immortal in culture. This capacity may demand avoidance of any imbalance in protein homeostasis (proteostasis) that would otherwise compromise stem cell identity. Here we show that human pluripotent stem cells exhibit enhanced assembly of the TRiC/CCT complex, a chaperonin that facilitates the folding of 10% of the proteome. We find that ectopic expression of a single subunit (CCT8) is sufficient to increase TRiC/CCT assembly. Moreover, increased TRiC/CCT complex is required to avoid aggregation of mutant Huntingtin protein. We further show that increased expression of CCT8 in somatic tissues extends Caenorhabditis elegans lifespan in a TRiC/CCT-dependent manner. Ectopic expression of CCT8 also ameliorates the age-associated demise of proteostasis and corrects proteostatic deficiencies in worm models of Huntington's disease. Our results suggest proteostasis is a common principle that links organismal longevity with hESC immortality.

PMID:
27892468
PMCID:
PMC5133698
DOI:
10.1038/ncomms13649
[Indexed for MEDLINE]
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20.
J Mol Med (Berl). 2016 Dec;94(12):1349-1358. Epub 2016 Nov 26.

Reducing RBM20 activity improves diastolic dysfunction and cardiac atrophy.

Author information

1
Neuromuscular and Cardiovascular Cell Biology, Max Delbrück Center for Molecular Medicine, Robert-Rössle-Str. 10, 13125, Berlin, Germany.
2
DZHK (German Center for Cardiovascular Research), partner site Berlin, Berlin, Germany.
3
Klaus Tschira Institute for Integrative Computational Cardiology and Department of Cardiology, Angiology, and Pneumology, Heidelberg University, Analysezentrum III, INF 669, 69120, Heidelberg, Germany.
4
DZHK (German Center for Cardiovascular Research), partner site Heidelberg, Heidelberg, Germany.
5
Department of Cellular and Molecular Medicine, University of Arizona, Arizona Health Sciences Center, 1501 N. Campbell, PO Box 245051, Tucson, AZ, 85724, USA.
6
Neuromuscular and Cardiovascular Cell Biology, Max Delbrück Center for Molecular Medicine, Robert-Rössle-Str. 10, 13125, Berlin, Germany. gotthardt@mdc-berlin.de.
7
DZHK (German Center for Cardiovascular Research), partner site Berlin, Berlin, Germany. gotthardt@mdc-berlin.de.

Abstract

Impaired diastolic filling is a main contributor to heart failure with preserved ejection fraction (HFpEF), a syndrome with increasing prevalence and no treatment. Both collagen and the giant sarcomeric protein titin determine diastolic function. Since titin's elastic properties can be adjusted physiologically, we evaluated titin-based stiffness as a therapeutic target. We adjusted RBM20-dependent cardiac isoform expression in the titin N2B knockout mouse with increased ventricular stiffness. A ~50 % reduction of RBM20 activity does not only maintain cardiac filling in diastole but also ameliorates cardiac atrophy and thus improves cardiac function in the N2B-deficient heart. Reduced RBM20 activity partially normalized gene expression related to muscle development and fatty acid metabolism. The adaptation of cardiac growth was related to hypertrophy signaling via four-and-a-half lim-domain proteins (FHLs) that translate mechanical input into hypertrophy signals. We provide a novel link between cardiac isoform expression and trophic signaling via FHLs and suggest cardiac splicing as a therapeutic target in diastolic dysfunction.

KEY MESSAGE:

Increasing the length of titin isoforms improves ventricular filling in heart disease. FHL proteins are regulated via RBM20 and adapt cardiac growth. RBM20 is a therapeutic target in diastolic dysfunction.

KEYWORDS:

Heart failure; Hypertrophy signaling; Mouse models; RNA processing; Therapy

PMID:
27889803
PMCID:
PMC5143357
DOI:
10.1007/s00109-016-1483-3
[Indexed for MEDLINE]
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