Article
Biochemistry & Molecular Biology
Yanghai Zhang, Chunyan Wang, Mingming Sun, Yutong Jin, Camila Urbano Braz, Hasan Khatib, Timothy A. Hacker, Martin Liss, Michael Gotthardt, Henk Granzier, Ying Ge, Wei Guo
Summary: Arginine-serine (RS) domains play critical roles in protein-protein interaction, splicing control, and nucleocytoplasmic transport. By using mass spectrometry, we identified 16 phosphorylation sites on RS domains, including two sites located in the RSRSP stretch. Mutations on these sites affected splicing, nucleocytoplasmic transport, and protein-RNA condensates. Our study also revealed that RBM20 mutations led to cardiac pathogenesis.
Article
Cardiac & Cardiovascular Systems
David C. Lennermann, Mark E. Pepin, Markus Grosch, Laura Konrad, Elena Kemmling, Joshua Hartmann, Janica L. Nolte, Sandra Clauder-Muenster, Elham Kayvanpour, Farbod Sedaghat-Hamedani, Jan Haas, Benjamin Meder, Malou van den Boogaard, Ahmad S. Amin, Matthias Dewenter, Marcus Krueger, Lars M. Steinmetz, Johannes Backs, Maarten M. G. van den Hoogenhof
Summary: This study investigates sex differences in RBM20 cardiomyopathy in an animal model and a patient cohort. The findings suggest that there are no functional differences between male and female RBM20 knockout mice, indicating that treatment should not differ between sexes. The study also shows that male RBM20 cardiomyopathy patients do not exhibit worse cardiac function compared to female patients.
AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY
(2022)
Review
Cardiac & Cardiovascular Systems
Na Li, Weijian Hang, Hongyang Shu, Ning Zhou
Summary: This review summarizes how RBM20 and other splicing factors modify the ratio of Titin isoforms, providing a promising therapeutic target for improving myocardial compliance in HFpEF.
FRONTIERS IN CARDIOVASCULAR MEDICINE
(2022)
Article
Cardiac & Cardiovascular Systems
Pablo Montanes-Agudo, Yigal M. Pinto, Esther E. Creemers
Summary: Alternative splicing generates specialized protein isoforms for heart adaptation. Mutations in RNA-binding protein 20 (RBM20) causing severe familial dilated cardiomyopathy have sparked interest in alternative splicing in cardiology. However, an integrated and systematic analysis of splicing networks of these factors is lacking.
JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY
(2023)
Article
Biochemistry & Molecular Biology
Rexiati Maimaiti, Chaoqun Zhu, Yanghai Zhang, Qiyue Ding, Wei Guo
Summary: This study revealed the differential expression of RBM20 across muscles and the muscle-type specificity of RBM20-mediated splicing. The research also found that the splicing of Ttn in response to hormones is influenced by the presence of RBM20, and that RBM20-mediated splicing mainly occurs through the genomic signaling pathway in C2C12 cells.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Article
Genetics & Heredity
Takuma Yamamoto, Rie Sano, Aya Miura, Mai Imasaka, Yoshiro Naito, Minori Nishiguchi, Kensuke Ihara, Naruhito Otani, Yoshihiko Kominato, Masaki Ohmuraya, Hidehito Kuroyanagi, Hajime Nishio
Summary: This study identified the manifestation of I536T-RBM20 variant in human patients and its effects in a mouse model. The variant alters gene splicing and affects gene expression, but does not cause dilated cardiomyopathy.
JOURNAL OF MOLECULAR MEDICINE-JMM
(2022)
Article
Biochemistry & Molecular Biology
Christophe Rachez, Rachel Legendre, Mickael Costallat, Hugo Varet, Jia Yi, Etienne Kornobis, Christian Muchardt
Summary: HP1 proteins, known for marking heterochromatin and gene silencing, are also RNA-binding proteins. HP1 gamma, in particular, is targeted to hexameric RNA motifs and SINE transposable elements, tethering unspliced pre-mRNA to chromatin through intronic regions and limiting the usage of intronic cryptic splice sites during transcription. This reveals new insights into the relationship between chromatin and co-transcriptional splicing.
Review
Immunology
Frank Fang Yao Lee, Scott Alper
Summary: While TLR signaling is necessary to combat infection, persistent inflammation can cause damage and contribute to various inflammatory disorders. Alternative pre-mRNA splicing plays a role in terminating TLR signaling by producing dominant negative inhibitors that limit inflammation. Understanding the production and function of these alternative isoforms may provide insights into inflammatory disease.
FRONTIERS IN IMMUNOLOGY
(2022)
Article
Multidisciplinary Sciences
Yang Pan, John W. Phillips, Beatrice D. Zhang, Miyako Noguchi, Eric Kutschera, Jami McLaughlin, Pavlo A. Nesterenko, Zhiyuan Mao, Nathanael J. Bangayan, Robert Wang, Wendy Tran, Harry T. Yang, Yuanyuan Wang, Yang Xu, Matthew B. Obusan, Donghui Cheng, Alex H. Lee, Kathryn E. Kadash-Edmondson, Ameya Champhekar, Cristina Puig-Saus, Antoni Ribas, Robert M. Prins, Christopher S. Seet, Gay M. Crooks, Owen N. Witte, Yi Xing
Summary: This study describes a computational platform called IRIS that can discover tumor antigens derived from alternative splicing, providing potential targets for TCR and CAR-T immunotherapies. Through the analysis of transcriptomics and immuno-peptidomics data, the study demonstrates that the predicted targets by IRIS can bind with HLA molecules. The study illustrates the contribution of alternative splicing to the repertoire of tumor antigens and demonstrates the utility of IRIS in discovering AS-derived antigens and expanding cancer immunotherapies.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2023)
Review
Pharmacology & Pharmacy
Jianguo Feng, Jianlong Zhou, Yunxiao Lin, Wenhua Huang
Summary: This article highlights the importance of heterogeneous nuclear ribonucleoprotein A1 (hnRNP A1) in regulating RNA metabolism and its dysregulation in various diseases. The selective binding sites of hnRNP A1 to RNA and DNA are summarized, along with the co-regulatory factors that interact with hnRNP A1. The potential therapeutic implications of targeting hnRNP A1 are discussed, including small-molecule drugs and biomedicines.
FRONTIERS IN PHARMACOLOGY
(2022)
Article
Clinical Neurology
Ainara Elorza, Yamile Marquez, Jorge R. Cabrera, Jose Luis Sanchez-Trincado, Maria Santos-Galindo, Ivo H. Hernandez, Sara Pico, Juan Diaz-Hernandez, Ramon Garcia-Escudero, Manuel Irimia, Jose J. Lucas
Summary: Correction of mis-splicing events is a promising therapeutic approach for neurological diseases caused by splicing-affecting mutations. Next-generation RNA sequencing has enabled the investigation of global mis-splicing in diseased tissue to identify key pathogenic mis-spliced genes. Our new intersect-RNA-seq approach captures pathogenic global mis-splicing in the Huntington's disease striatum.
Article
Cardiac & Cardiovascular Systems
Lili Zhu, Krishna Choudhary, Barbara Gonzalez-Teran, Yen-Sin Ang, Reuben Thomas, Nicole R. Stone, Lei Liu, Ping Zhou, Chenchen Zhu, Hongmei Ruan, Yu Huang, Shibo Jin, Angelo Pelonero, Frances Koback, Arun Padmanabhan, Nandhini Sadagopan, Austin Hsu, Mauro W. Costa, Casey A. Gifford, Joke van Bemmel, Ruth Huttenhain, Vasanth Vedantham, Bruce R. Conklin, Brian L. Black, Benoit G. Bruneau, Lars Steinmetz, Nevan J. Krogan, Katherine S. Pollard, Deepak Srivastava
Summary: This study reveals that GATA4 regulates cell type-specific alternative splicing in human induced pluripotent stem cell-derived cardiac progenitors through direct interaction with RNA and the spliceosome.
Article
Biochemistry & Molecular Biology
Jing Liu, Ke Wang, Xingyang Liu, Lei Pan, Wanlu Zhou, Jingru Huang, Hongli Liu, Zhiying Su, Xiu Qin Xu
Summary: It has been found that RNA binding motif protein 24 (RBM24) is a key regulator of CaMKII delta splicing, playing a crucial role in the heart. Loss of RBM24 leads to abnormal shift of CaMKII delta towards the delta-C isoform, affecting Ca2+ handling and prolonging the ventricular cardiac action potential and QT interval.
CELLULAR AND MOLECULAR LIFE SCIENCES
(2022)
Article
Cardiac & Cardiovascular Systems
Alexander A. A. Akerberg, Michael Trembley, Vincent Butty, Asya Schwertner, Long Zhao, Manu Beerens, Xujie Liu, Mohammed Mahamdeh, Shiaulou Yuan, Laurie Boyer, Calum MacRae, Christopher Nguyen, William T. T. Pu, Caroline E. E. Burns, C. Geoffrey Burns
Summary: This study identified RBPMS2 as a key regulator of alternative splicing, myofibrillar organization, and calcium handling in zebrafish and human cardiomyocytes.
CIRCULATION RESEARCH
(2022)
Review
Oncology
Benoit Soubise, Yan Jiang, Nathalie Douet-Guilbert, Marie-Berengere Troadec
Summary: RBM22 is a gene that encodes an RNA-binding protein involved in RNA splicing, transcription, and gene regulation. Mutations and changes in dosage of RBM22 are associated with various diseases, particularly cancer. RBM22 has the potential to be a therapeutic target for specific diseases, including cancer.
Article
Cardiac & Cardiovascular Systems
N. M. Quaife, S. Chothani, J. F. Schulz, E. L. Lindberg, K. Vanezis, E. Adami, K. O'Fee, J. Greiner, M. Litvinukova, S. van Heesch, N. Whiffin, N. Hubner, S. Schafer, O. Rackham, S. A. Cook, P. J. R. Barton
Summary: This study investigates the role of small open reading frames (smORFs) in myocardial fibroblast activation and identifies a novel mechanism mediated by LINC01013 smORF micropeptide.
JOURNAL OF CARDIOVASCULAR TRANSLATIONAL RESEARCH
(2023)
Article
Biochemistry & Molecular Biology
Toray S. Akcan, Sergey Vilov, Matthias Heinig
Summary: DNA and RNA-binding trans-acting factors play a crucial role in regulating promoter-proximal RNA polymerase II (Pol II) pausing, which is a rate-limiting step in gene expression. In this study, we developed a machine learning model that accurately predicts the extent of Pol II pausing based on genomic and transcriptomic data, and identified previously unknown regulators of pausing.
NUCLEIC ACIDS RESEARCH
(2023)
Article
Biology
Sarah Nordmeyer, Milena Kraus, Matthias Ziehm, Marieluise Kirchner, Marie Schafstedde, Marcus Kelm, Sylvia Niquet, Mariet Mathew Stephen, Istvan Baczko, Christoph Knosalla, Matthieu-P Schapranow, Gunnar Dittmar, Michael Gotthardt, Martin Falcke, Vera Regitz-Zagrosek, Titus Kuehne, Philipp Mertins
Summary: Pressure overload and volume overload in heart valve diseases lead to specific forms of cardiac remodeling. Proteome profiling of human left ventricular myocardial biopsies revealed differences in protein composition compared to controls, particularly in the areas of extracellular matrix, cytoskeleton, energy metabolism, and proteostasis. Sex-specific differences were also observed. These findings provide insight into the molecular mechanisms of cardiac remodeling in patients with heart valve diseases, which could help in developing personalized treatment strategies.
LIFE SCIENCE ALLIANCE
(2023)
Article
Virology
Hella Schwanke, Vladimir Goncalves Magalhaes, Stefan Schmelz, Emanuel Wyler, Thomas Hennig, Thomas Guenther, Adam Grundhoff, Lars Doelken, Markus Landthaler, Marco van Ham, Lothar Jaensch, Konrad Buessow, Joop van den Heuvel, Wulf Blankenfeldt, Caroline C. Friedel, Florian Erhard, Melanie M. Brinkmann
Summary: Replication of human cytomegalovirus (HCMV) can have serious consequences for fetal development in immunosuppressed individuals. This study focuses on the M35 protein of murine cytomegalovirus (MCMV), which suppresses the host's antiviral response by interfering with the induction of type I interferons (IFNs). The researchers determined the crystal structure of M35 and found that its dimerization is crucial for its immunomodulatory activity. M35 was shown to bind to the regulatory DNA element that controls the transcription of the first type I IFN gene, thereby antagonizing gene induction by interferon regulatory factor 3 (IRF3). Evaluation: 6.5/10.
JOURNAL OF VIROLOGY
(2023)
Article
Biochemistry & Molecular Biology
Clara-L. Sandmann, Jana F. Schulz, Jorge Ruiz-Orera, Marieluise Kirchner, Matthias Ziehm, Eleonora Adami, Maike Marczenke, Annabel Christ, Nina Liebe, Johannes Greiner, Aaron Schoenenberger, Michael B. Muecke, Ning Liang, Robert L. Moritz, Zhi Sun, Eric W. Deutsch, Michael Gotthardt, Jonathan M. Mudge, John R. Prensner, Thomas E. Willnow, Philipp Mertins, Sebastiaan van Heesch, Norbert Hubner
Summary: This study analyzes the evolutionary origins of 7,264 recently cataloged human short open reading frames (sORFs) and finds that most of them are evolutionarily young and emerged de novo. The researchers also identify 221 previously missed sORFs that potentially encode peptides smaller than the smallest annotated human microprotein. By conducting mass-spectrometry-based interactome screens and cellular assays, the study associates some of these sORFs with mRNA splicing, translational regulation, and endocytosis-related functions.
Article
Multidisciplinary Sciences
Markus Grosch, Laura Schraft, Adrian Chan, Leonie Kuechenhoff, Kleopatra Rapti, Anne-Maud Ferreira, Julia Kornienko, Shengdi Li, Michael H. Radke, Chiara Kraemer, Sandra Clauder-Muenster, Emerald Perlas, Johannes Backs, Michael Gotthardt, Christoph Dieterich, Maarten M. G. van den Hoogenhof, Dirk Grimm, Lars M. Steinmetz
Summary: Dilated cardiomyopathy can be repaired using CRISPR gene therapy, but challenges with delivery and off-target effects have limited its applicability. By combining AAVMYO viral vector with CRISPR base editors, we repaired patient mutations in the cardiac splice factor Rbm20. Treatment restored cardiac function and showed no evidence of off-target editing.
NATURE COMMUNICATIONS
(2023)
Article
Genetics & Heredity
Kathryn A. Mcgurk, Xiaolei Zhang, Pantazis Theotokis, Kate Thomson, Andrew Harper, Rachel J. Buchan, Erica Mazaika, Elizabeth Ormondroyd, William T. Wright, Daniela Macaya, Chee Jian Pua, Birgit Funke, Daniel G. Macarthur, Sanjay K. Prasad, Stuart A. Cook, Mona Allouba, Yasmine Aguib, Magdi H. Yacoub, Declan P. O'Regan, Paul J. R. Barton, Hugh Watkins, Leonardo Bottolo, James S. Ware
Summary: Understanding the penetrance of pathogenic variants identified as secondary findings is crucial in managing individuals undergoing genetic screening. Through large-scale analysis of genetic variants in patients with hypertrophic cardiomyopathy and dilated cardiomyopathy, the study provides estimates of penetrance and identifies variants with higher penetrance that should be considered.
AMERICAN JOURNAL OF HUMAN GENETICS
(2023)
Article
Cardiac & Cardiovascular Systems
Mona Allouba, Roddy Walsh, Alaa Afify, Mohammed Hosny, Sarah Halawa, Aya Galal, Mariam Fathy, Pantazis Theotokis, Ahmed Boraey, Amany Ellithy, Rachel Buchan, Risha Govind, Nicola Whiffin, Shehab Anwer, Ahmed ElGuindy, James S. Ware, Paul J. R. Barton, Magdi Yacoub, Yasmine Aguib
Summary: This study aims to define the genetic architecture of hypertrophic cardiomyopathy (HCM) in North African populations with high consanguinity by comparing with ancestry-matched cases and controls. The results show a higher prevalence of homozygous variants in Egyptian patients, with minor HCM genes more likely to present in homozygosity. Rare variants in Egyptian HCM patients were less likely to be classified as (likely) pathogenic compared to Europeans. The incorporation of ancestry-matched controls improves the classification of genetic variants in HCM patients.
EUROPEAN HEART JOURNAL
(2023)
Article
Multidisciplinary Sciences
Julia Kornienko, Marta Rodriguez-Martinez, Kai Fenzl, Florian Hinze, Daniel Schraivogel, Markus Grosch, Brigit Tunaj, Dominik Lindenhofer, Laura Schraft, Moritz Kueblbeck, Eric Smith, Chad Mao, Emily Brown, Anjali Owens, Ardan M. M. Saguner, Benjamin Meder, Victoria Parikh, Michael Gotthardt, Lars M. M. Steinmetz
Summary: The authors demonstrate that loss of interaction with the nuclear importer TNPO3 leads to cytoplasmic mislocalization of RBM20 variants associated with severe dilated cardiomyopathy. Restoring their nuclear localization can alleviate the disease phenotype. These findings provide insight into the molecular mechanism of RBM20 mislocalization and its role in dilated cardiomyopathy.
NATURE COMMUNICATIONS
(2023)
Article
Biochemistry & Molecular Biology
Fabian Freiberg, Meghna Thakkar, Wiebke Hamann, Jacobo Lopez Carballo, Rene Juettner, Felizia K. Voss, Peter M. Becher, Dirk Westermann, Carsten Tschoepe, Arnd Heuser, Oliver Rocks, Robert Fischer, Michael Gotthardt
Summary: Heart attack leads to the death of heart muscle cells, causing lesions that turn into fibrotic tissue. Inhibiting the cell contact protein CAR can limit the damage and improve survival in patients with myocardial infarction, suggesting it as a potential therapeutic target.
EXPERIMENTAL AND MOLECULAR MEDICINE
(2023)
Article
Biochemical Research Methods
Sergey Vilov, Matthias Heinig
Summary: In this study, a convolutional neural network-based approach called DeepSom is presented for detecting somatic single nucleotide polymorphism and short insertion and deletion variants in tumor whole-genome sequencing samples without a matched normal. The performance of DeepSom is validated on five different cancer datasets and it is demonstrated to outperform previously proposed methods for tumor-only somatic variant calling on whole-genome sequencing samples.
Article
Biotechnology & Applied Microbiology
Shuang Li, Katharina T. Schmid, Dylan H. de Vries, Maryna Korshevniuk, Corinna Losert, Roy Oelen, Irene van Blokland, Hilde E. Groot, Morris A. Swertz, Pim van der Harst, Harm-Jan Westra, Monique G. P. van der Wijst, Matthias Heinig, Lude Franke
Summary: This study uses single-cell data to reconstruct personalized co-expression networks and identifies SNPs altering co-expression patterns. These co-eQTLs are replicated in a large bulk cohort and provide novel insights into disease-associated variants and regulatory networks.
Article
Biochemistry & Molecular Biology
Mark Sweeney, Katie O'Fee, Chelsie Villanueva-Hayes, Ekhlas Rahman, Michael Lee, Konstantinos Vanezis, Ivan Andrew, Wei-Wen Lim, Anissa Widjaja, Paul J. R. Barton, Stuart A. Cook
Summary: This study demonstrates that IL11 expression in cardiomyocytes can lead to severe cardiac fibrosis and inflammation, as well as endothelial-to-mesenchymal transition and left ventricular dysfunction.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Multidisciplinary Sciences
Florin Ratajczak, Mitchell Joblin, Marcel Hildebrandt, Martin Ringsquandl, Pascal Falter-Braun, Matthias Heinig
Summary: Understanding phenotype-genotype relationships is a challenge in biology, and the authors use graph representation learning to identify human genes with core gene characteristics for complex diseases. The core-like genes exhibit similar properties to core genes and are attractive targets for drug development.
NATURE COMMUNICATIONS
(2023)
Meeting Abstract
Biochemistry & Molecular Biology
Mona Allouba, Roddy Walsh, Alaa Afify, Sarah Halawa, Aya Galal, Mohammed Hosny, Mariam Fathy, Pantazis Theotokis, Amany Ellithy, Rachel Buchan, Risha Govind, Nicola Whiffin, Shehab Anwer, Ahmed El Guindy, James Ware, Paul Barton, Yasmine Aguib, Magdi H. Yacoub
EUROPEAN JOURNAL OF HUMAN GENETICS
(2023)