Cardiovascular disease is the most common cause of death worldwide, but despite improved prevention and therapy, the incidence of heart failure continues to rise. The most severe forms are genetic and include mutations that affect the protein makeup of cardiomyocytes through a mechanism called alternative splicing. This can result in impaired filling, contraction, and sudden cardiac death. Alternative splicing determines which mature RNA transcripts drive the mechanical, structural, signaling, and metabolic properties of the heart.
Here, we will utilize advances in RNA sequencing technologies to study cardiac splicing in mouse, python, human engineered heart tissue and patient samples, paired with targeted network and functional analysis. The resulting splice regulatory network will provide a basis for the identification of novel drug targets and to identify disease-related and disease-causing alternative splicing events in cardiomyopathy.
Translating our findings to improve patient care, we will study how alternative splicing is regulated in the heart and how it contributes to cardiac adaptation in the developing mouse embryo and during exercise. As a model for ‘exaggerated’ hypertrophy and regression we will rely on the python, which will allow the identification of proteins with central roles in the regulatory network that cause the strongest physiological effect. We will compare alternative splicing in such models of healthy adaptation vs. disease to improve personalized diagnosis and therapy of heart disease.
Michael Gotthardt
Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association (MDC) (Germany)
Leslie Leinwand
The Regents of the University of Colorado (USA)
Euan Ashley
Stanford University (USA)
Maria Carmo-Fonseca
Instituto de Medicina Molecular (Institute of Molecular Medicine) (Portugal)
Benjamin Meder
Universitätsklinikum und Medizinische Fakultät Heidelberg (Germany)
Lars Steinmetz
Stanford University (USA)
© CU boulder
BioFrontiers Institute, CU Boulder (USA)
Leslie's laboratory aims to understand the mechanisms of genetic heart and skeletal muscle diseases, as well as the processes driving maladaptive and adaptive cardiac hypertrophy in several different model systems including the Burmese python.
© Max-Delbrück-Center
Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association, Berlin (Germany)
Mitch's laboratory studies how alternative splicing relates to diastolic heart failure, how increased filling of the cardiac ventricle leads to improved contraction (Frank-Starling mechanism of the heart), and how the electrical properties of the heart and mechanoelectrical coupling are regulated.
© Stanford University
Stanford University (USA)
Euan's group studies the human genome and applies computational approaches like machine learning to understand the integrated effects of genes and proteins on human health and disease, with a specific focus on cardiac biology.
© Instituto de Medicina Molecular
Instituto de Medicina Molecular, Lisbon (Portugal)
Carmo's laboratory focuses on RNA splicing and its role in the regulation of gene expression in cancer and genetic diseases.
© Universitätsklinikum Heidelberg
Universitätsklinikum Heidelberg (Germany)
Benjamin's group combines functional genomics, next-generation genetic testing and nucleic acid biomarker development to better understand the molecular basis of cardiomyopathies.
© Stanford University
Stanford (USA) / EMBL (Heidelberg)
Lars's group develops experimental approaches to read, edit and write entire genomes across scales. By applying these technologies, they aim to understand the genetic basis of complex phenotypes, the mechanisms of gene regulation and RNA splicing, and the molecular systems underpinning disease.
Properly timed gene expression is essential for all aspects of organismal physiology. Despite significant progress, our understanding of the complex mechanisms governing the dynamics of gene regulation in response to internal and external signals remains incomplete. Over the past decade, advances in technologies like light and cryo-electron microscopy (Cryo-EM), cryo-electron tomography (Cryo-ET) and high-throughput sequencing have spurred new insights into traditional paradigms of gene expression. In this Review, we delve into recent concepts addressing 'where' and 'when' gene transcription and RNA splicing occur within cells, emphasizing the dynamic spatial and temporal organization of the cell nucleus.
https://pubmed.ncbi.nlm.nih.gov/40019352/
Hypertrophic cardiomyopathy (HCM) is the most prevalent inherited cardiomyopathy and a leading cause of sudden death. Genetic testing and familial cascade screening play a pivotal role in the clinical management of HCM patients. However, conventional genetic tests primarily focus on the detection of exonic and canonical splice site variation. Oversighting intronic non-canonical splicing variants potentially contributes to a proportion of HCM patients remaining genetically undiagnosed. Here, using a non-integrative reprogramming strategy, we generated induced pluripotent stem cell (iPSC) lines from four individuals carrying one of two variants within intronic regions of MYBPC3: c.1224-52G > A and c.1898-23A > G. Upon differentiation to iPSC-derived cardiomyocytes (iPSC-CMs), mis-spliced mRNAs were identified in cells harbouring these variants. Both abnormal mRNAs contained a premature termination codon (PTC), fitting the criteria for activation of nonsense mediated decay (NMD). However, the c.1898-23A > G transcripts escaped this mRNA quality control mechanism, while the c.1224-52G > A transcripts were degraded. The newly generated iPSC lines represent valuable tools for studying the functional consequences of intronic variation and for translational research aimed at reversing splicing abnormalities to prevent disease progression.
https://pubmed.ncbi.nlm.nih.gov/39447317/
As ambush-hunting predators that consume large prey after long intervals of fasting, Burmese pythons evolved with unique adaptations for modulating organ structure and function. Among these is cardiac hypertrophy that develops within three days following a meal (Andersen et al., 2005, Secor, 2008), which we previously showed was initiated by circulating growth factors (Riquelme et al., 2011). Postprandial cardiac hypertrophy in pythons also rapidly regresses with subsequent fasting (Secor, 2008); however, the molecular mechanisms that regulate the dynamic cardiac remodeling in pythons during digestion are largely unknown. In this study, we employed a multiomics approach coupled with targeted molecular analyses to examine remodeling of the python ventricular transcriptome and proteome throughout digestion. We found that forkhead box protein O1 (FoxO1) signaling was suppressed prior to hypertrophy development and then activated during regression, which coincided with decreased and then increased expression, respectively, of FoxO1 transcriptional targets involved in proteolysis. To define the molecular mechanistic role of FoxO1 in hypertrophy regression, we used cultured mammalian cardiomyocytes treated with postfed python plasma. Hypertrophy regression both in pythons and in vitro coincided with activation of FoxO1-dependent autophagy; however, the introduction of a FoxO1-specific inhibitor prevented both regression of cell size and autophagy activation. Finally, to determine whether FoxO1 activation could induce regression, we generated an adenovirus expressing a constitutively active FoxO1. FoxO1 activation was sufficient to prevent and reverse postfed plasma-induced hypertrophy, which was partially prevented by autophagy inhibition. Our results indicate that modulation of FoxO1 activity contributes to the dynamic ventricular remodeling in postprandial Burmese pythons.
Some vertebrates evolved to have a remarkable capacity for anatomical and physiological plasticity in response to environmental challenges. One example of such plasticity can be found in the ambush-hunting snakes of the genus Python, which exhibit reversible cardiac growth with feeding. The predation strategy employed by pythons is associated with months-long fasts that are arrested by ingestion of large prey. Consequently, digestion compels a dramatic increase in metabolic rate and hypertrophy of multiple organs, including the heart. In this Review, we summarize the post-prandial cardiac adaptations in pythons at the whole-heart, cellular and molecular scales. We highlight circulating factors and cellular signaling pathways that are altered during digestion to affect cardiac form and function and propose possible mechanisms that may drive the post-digestion regression of cardiac mass. Adaptive physiological cardiac hypertrophy has also been observed in other vertebrates, including in fish acclimated to cold water, birds flying at high altitudes and exercising mammals. To reveal potential evolutionarily conserved features, we summarize the molecular signatures of reversible cardiac remodeling identified in these species and compare them with those of pythons. Finally, we offer a perspective on the potential of biomimetics targeting the natural biology of pythons as therapeutics for human heart disease.
Cardiac blood flow is a critical determinant of human health. However, the definition of its genetic architecture is limited by the technical challenge of capturing dynamic flow volumes from cardiac imaging at scale. We present DeepFlow, a deep-learning system to extract cardiac flow and volumes from phase-contrast cardiac magnetic resonance imaging. A mixed-linear model applied to 37,653 individuals from the UK Biobank reveals genome-wide significant associations across cardiac dynamic flow volumes spanning from aortic forward velocity to aortic regurgitation fraction. Mendelian randomization reveals a causal role for aortic root size in aortic valve regurgitation. Among the most significant contributing variants, localizing genes (near ELN, PRDM6 and ADAMTS7) are implicated in connective tissue and blood pressure pathways. Here we show that DeepFlow cardiac flow phenotyping at scale, combined with genotyping data, reinforces the contribution of connective tissue genes, blood pressure and root size to aortic valve function.
Purpose of review: The introduction of Artificial Intelligence into the healthcare system offers enormous opportunities for biomedical research, the improvement of patient care, and cost reduction in high-end medicine. Digital concepts and workflows are already playing an increasingly important role in cardiology. The fusion of computer science and medicine offers great transformative potential and enables enormous acceleration processes in cardiovascular medicine.
Recent findings: As medical data becomes smart, it is also becoming more valuable and vulnerable to malicious actors. In addition, the gap between what is technically possible and what is allowed by privacy legislation is growing. Principles of the General Data Protection Regulation that have been in force since May 2018, such as transparency, purpose limitation, and data minimization, seem to hinder the development and use of Artificial Intelligence. Concepts to secure data integrity and incorporate legal and ethical principles can help to avoid the potential risks of digitization and may result in an European leadership in regard to privacy protection and AI. The following review provides an overview of relevant aspects of Artificial Intelligence and Machine Learning, highlights selected applications in cardiology, and discusses central ethical and legal considerations.
Severe forms of dilated cardiomyopathy (DCM) are associated with point mutations in the alternative splicing regulator RBM20 that are frequently located in the arginine/serine-rich domain (RS-domain). Such mutations can cause defective splicing and cytoplasmic mislocalization, which leads to the formation of detrimental cytoplasmic granules. Successful development of personalized therapies requires identifying the direct mechanisms of pathogenic RBM20 variants. Here, we decipher the molecular mechanism of RBM20 mislocalization and its specific role in DCM pathogenesis. We demonstrate that mislocalized RBM20 RS-domain variants retain their splice regulatory activity, which reveals that aberrant cellular localization is the main driver of their pathological phenotype. A genome-wide CRISPR knockout screen combined with image-enabled cell sorting identified Transportin-3 (TNPO3) as the main nuclear importer of RBM20. We show that the direct RBM20-TNPO3 interaction involves the RS-domain, and is disrupted by pathogenic variants. Relocalization of pathogenic RBM20 variants to the nucleus restores alternative splicing and dissolves cytoplasmic granules in cell culture and animal models. These findings provide proof-of-principle for developing therapeutic strategies to restore RBM20's nuclear localization in RBM20-DCM patients.
Dilated cardiomyopathy is the second most common cause for heart failure with no cure except a high-risk heart transplantation. Approximately 30% of patients harbor heritable mutations which are amenable to CRISPR-based gene therapy. However, challenges related to delivery of the editing complex and off-target concerns hamper the broad applicability of CRISPR agents in the heart. We employ a combination of the viral vector AAVMYO with superior targeting specificity of heart muscle tissue and CRISPR base editors to repair patient mutations in the cardiac splice factor Rbm20, which cause aggressive dilated cardiomyopathy. Using optimized conditions, we repair >70% of cardiomyocytes in two Rbm20 knock-in mouse models that we have generated to serve as an in vivo platform of our editing strategy. Treatment of juvenile mice restores the localization defect of RBM20 in 75% of cells and splicing of RBM20 targets including TTN. Three months after injection, cardiac dilation and ejection fraction reach wild-type levels. Single-nuclei RNA sequencing uncovers restoration of the transcriptional profile across all major cardiac cell types and whole-genome sequencing reveals no evidence for aberrant off-target editing. Our study highlights the potential of base editors combined with AAVMYO to achieve gene repair for treatment of hereditary cardiac diseases.
Despite advances in therapeutics for heart failure and arrhythmias, a substantial proportion of patients with cardiomyopathy do not respond to interventions, indicating a need to identify novel modifiable myocardial pathobiology. Human genetic variation associated with severe forms of cardiomyopathy and arrhythmias has highlighted the crucial role of alternative splicing in myocardial health and disease, given that it determines which mature RNA transcripts drive the mechanical, structural, signalling and metabolic properties of the heart. In this Review, we discuss how the analysis of cardiac isoform expression has been facilitated by technical advances in multiomics and long-read and single-cell sequencing technologies. The resulting insights into the regulation of alternative splicing — including the identification of cardiac splice regulators as therapeutic targets and the development of a translational pipeline to evaluate splice modulators in human engineered heart tissue, animal models and clinical trials — provide a basis for improved diagnosis and therapy. Finally, we consider how the medical and scientific communities can benefit from facilitated acquisition and interpretation of splicing data towards improved clinical decision-making and patient care.
To adapt to changing hemodynamic demands, regulatory mechanisms modulate actin-myosin-kinetics by calcium-dependent and -independent mechanisms. We investigate the posttranslational modification of human essential myosin light chain (ELC) and identify NIMA-related kinase 9 (NEK9) to interact with ELC. NEK9 is highly expressed in the heart and the interaction with ELC is calcium-dependent. Silencing of NEK9 results in blunting of calcium-dependent ELC-phosphorylation. CRISPR/Cas9-mediated disruption of NEK9 leads to cardiomyopathy in zebrafish. Binding to ELC is mediated via the protein kinase domain of NEK9. A causal relationship between NEK9 activity and ELC-phosphorylation is demonstrated by genetic sensitizing in-vivo. Finally, we observe significantly upregulated ELC-phosphorylation in dilated cardiomyopathy patients and provide a unique map of human ELC-phosphorylation-sites. In summary, NEK9-mediated ELC-phosphorylation is a calcium-dependent regulatory system mediating cardiac contraction and inotropy.
Dilated cardiomyopathy (DCM), a myocardial disease, is heterogeneous and often results in heart failure and sudden cardiac death. Unavailability of cardiac tissue has hindered the comprehensive exploration of gene regulatory networks and nodal players in DCM. In this study, we carried out integrated analysis of transcriptome and methylome data using non-negative matrix factorization from a cohort of DCM patients to uncover underlying latent factors and covarying features between whole-transcriptome and epigenome omics datasets from tissue biopsies of living patients. DNA methylation data from Infinium HM450 and mRNA Illumina sequencing of n = 33 DCM and n = 24 control probands were filtered, analyzed and used as input for matrix factorization using R NMF package. Mann-Whitney U test showed 4 out of 5 latent factors are significantly different between DCM and control probands (P<0.05). Characterization of top 10% features driving each latent factor showed a significant enrichment of biological processes known to be involved in DCM pathogenesis, including immune response (P = 3.97E-21), nucleic acid binding (P = 1.42E-18), extracellular matrix (P = 9.23E-14) and myofibrillar structure (P = 8.46E-12). Correlation network analysis revealed interaction of important sarcomeric genes like Nebulin, Tropomyosin alpha-3 and ERC-protein 2 with CpG methylation of ATPase Phospholipid Transporting 11A0, Solute Carrier Family 12 Member 7 and Leucine Rich Repeat Containing 14B, all with significant P values associated with correlation coefficients >0.7. Using matrix factorization, multi-omics data derived from human tissue samples can be integrated and novel interactions can be identified. Hypothesis generating nature of such analysis could help to better understand the pathophysiology of complex traits such as DCM.
Cellular mRNA-binding proteins (mRBPs) are major posttranscriptional regulators of gene expression. Although many posttranslational modification sites in mRBPs have been identified, little is known about how these modifications regulate mRBP function. Here, we developed quantitative RNA-interactome capture (qRIC) to quantify the fraction of mRBPs pulled down with polyadenylated mRNAs. Combining qRIC with phosphoproteomics allowed us to systematically compare pull-down efficiencies of phosphorylated and nonphosphorylated forms of mRBPs. Almost 200 phosphorylation events affected pull-down efficiency compared with the unmodified mRBPs and thus have regulatory potential. Our data capture known regulatory phosphorylation sites in ELAVL1, SF3B1, and UPF1 and identify potential regulatory sites. Follow-up experiments on the splicing regulator RBM20 revealed multiple phosphorylation sites in the C-terminal disordered region affecting nucleocytoplasmic localization, association with cytoplasmic ribonucleoprotein granules, and alternative splicing. Together, we show that qRIC in conjunction with phosphoproteomics is a scalable method to identify functional posttranslational modification sites in mRBPs.
As an opportunistic predator, the Burmese python (Python molurus bivittatus) consumes large and infrequent meals, fasting for up to a year. Upon consuming a large meal, the Burmese python exhibits extreme metabolic responses. To define the pathways that regulate these postprandial metabolic responses, we performed a comprehensive profile of plasma metabolites throughout the digestive process. Following ingestion of a meal equivalent to 25% of its body mass, plasma lipoproteins and metabolites, such as chylomicra and bile acids, reach levels observed only in mammalian models of extreme dyslipidemia. Here, we provide evidence for an adaptive response to postprandial nutrient overload by the python liver, a critical site of metabolic homeostasis. The python liver undergoes a substantial increase in mass through proliferative processes, exhibits hepatic steatosis, hyperlipidemia-induced insulin resistance indicated by PEPCK activation and pAKT deactivation, and de novo fatty acid synthesis via FASN activation. This postprandial state is completely reversible. We posit that Burmese pythons evade the permanent hepatic damage associated with these metabolic states in mammals using evolved protective measures to inactivate these pathways. These include a transient activation of hepatic nuclear receptors induced by fatty acids and bile acids, including PPAR and FXR, respectively. The stress-induced p38 MAPK pathway is also transiently activated during the early stages of digestion. Taken together, these data identify a reversible metabolic response to hyperlipidemia by the python liver, only achieved in mammals by pharmacologic intervention. The factors involved in these processes may be relevant to or leveraged for remediating human hepatic pathology.
Splice regulators play an essential role in the transcriptomic diversity of all eukaryotic cell types and organ systems. Recent evidence suggests a contribution of splice-regulatory networks in many diseases, such as cardiomyopathies. Adaptive splice regulators, such as RNA-binding motif protein 20 (RBM20) determine the physiological mRNA landscape formation, and rare variants in the RBM20 gene explain up to 6% of genetic dilated cardiomyopathy (DCM) cases. With ample knowledge from RBM20-deficient mice, rats, swine and induced pluripotent stem cells (iPSCs), the downstream targets and quantitative effects on splicing are now well-defined and the prerequisites for corrective therapeutic approaches are set. This review article highlights some of the recent advances in the field, ranging from aspects of granule formation to 3D genome architectures underlying RBM20-related cardiomyopathy. Promising therapeutic strategies are presented and put into context with the pathophysiological characteristics of RBM20-related diseases.
Our next in-person network meeting will take place in Boulder, Colorado May 20-24th.
On Tuesday, May 6th, we will have presentations by Timothy Tse (PhD student in the Gotthardt lab, MDC Berlin) and Victor Badillo Lisakowski (Postdoc in the Gotthardt lab, MDC Berlin) at our monthly online junior meeting. Timothy will present on Quantifying RNA-protein interactions with CLIP and Victor will present on Alternative RBM20 isoforms in cardiac development and disease.
On Tuesday, April 1st, we will hear from Dakota Hunt (PhD Student in the Leinwand lab, CU Boulder) and Julia Kornienko (Postdoc in the Steinmetz lab, EMBL) during our monthly online junior meeting. Dakota will discuss Molecular Mechanisms of Postprandial Cardiac Adaptation in Pythons and Julia will discuss RBM20 Mislocalization in Dilated Cardiomyopathy.
Tuesday March 4th will be our next monthly junior online meeting. Presentations will be by Dominik Lindenhofer (Postdoc in the Steinmetz EMBL lab) and Pedro Prudêncio (Postdoc in the Carmo-Fonseca lab, GIMM). Dominik will be presenting on Functional phenotyping of genomic variants using multiomics scDNA-scRNA-seq and Pedro will be presenting an update on Natural antisense transcription in the Titin locus.
In-person network meetings:
May 20-24, 2025 in Boulder, Colorado USA
October 7-10, 2025 in Heidelberg, Germany
Our next CASTT online junior meeting will take place on February 4th. We will have a sandbox session on mastering the pores by GIMM (Lisbon) PhD student Marta Furtado and a presentation on identification of target transcripts for STAR family splicing factors by Uni Klinik Heidelberg senior scientist Abdullah Yalcin.
Tuesday, January 7th will be our first junior meeting of 2025. Linda Müller (Steinmetz lab, EMBL) will present on RBM20 Variant Effects on Splicing and Pragati Nalinkumar Parakkat (Gotthardt lab, Berlin) will present on Molecular Insights into Developmental Hypoxia and Cardiac Splicing Dynamics.
Our CASTT online junior meeting will take place on December 3rd. Arash Keshavarzi (Ashley lab, Stanford) will explore ideas in cardiomyopathy diagnostics using splicing data. Joshua Gillard (Ashley lab, Stanford) will discuss the article "SpliceTransformer predicts tissue-specific splicing linked to human disease."
Our 2nd network meeting for the year will take place in Lisbon, Portugal during the week of November 11-15.
Tuesday, November 5th will be our next online junior meeting. Bruna Gomes (Ashley lab, Stanford) will be continuing her talk from last month on the genetic architecture of two extremes: from myocardial fibrosis to peak physical performance and Liliia Demianenko (Gotthardt lab, MDC Berlin) will be leading a sandbox session on spatial insights into cardiac splicing.
Our next online junior meeting will be held on Tuesday, October 1st. Bruna Gomes (Ashley lab, Stanford) will be uncovering the genetic architecture of two extremes: from myocardial fibrosis to peak physical performance and Stefan Meinke (Gotthardt lab, MDC Berlin) will be discussing progress towards a comprehensive cardiac splicing network.
We are starting a new idea of sandbox sessions during our monthly online meetings every other month. The first session will be lead by postdoc Tommy Martin from the Leinwand lab at CU Boulder on RBM20 at this month's junior meeting. We will also have a presentation by postdoc Yuta Yamamoto from the Stanford Ashley lab on scalable assays to decode multiplexed variant effect of MYBPC3.
For our next upcoming monthly junior meeting, we will hear from PhD students Maryam Aghadi in the Gotthardt lab and Anastasiia Korosteleva in the Steinmetz lab at EMBL. Maryam will be discussing post MI splice network regulating cardiac remodeling and Anastasiia will be discussing single cell dissection of gene editing and cellular interactions in DCM.
Upcoming monthly junior presentation schedule:
Date | Presenter 1 | Presenter 2 |
June 4, 2024 | break | after midterm meeting |
July 2, 2024 | Maryam Aghadi (Gotthardt lab) | Anastasiia Korosteleva (Steinmetz lab) |
Aug 6, 2024 | Summer break | Summer break |
Sept 3, 2024 | Yuta Yamamoto (Ashley lab) | Tommy Martin (Leinwand lab)
|
Oct 1, 2024 | Beatriz Silva (Fonseca lab) | Arash Keshavarzi (Ashley lab) |
Nov 5, 2024 | Quentin McAfee (Leinwand lab) | Liliia Demianenko (Gotthardt lab)
|
Dec 3, 2024 | Stefan Meinke (Gotthardt lab) | Pedro Prudêncio (Fonseca lab) |
Jan 7, 2025 | Linda Mueller (Steinmetz lab) | Adelya Gabdulkhakova (Meder lab)
|
The CASTT midterm network meeting took place in Berlin at BIMSB from May 28-30.
Our next monthly online junior meeting will be on May 7. We will have CU Boulder Postdoc Thomas Martin presenting on a favorable response to LVAD therapy linked to alternative splicing and phosphorylation of CaMK2δ and iMM Lisbon PhD student Marta Furtado presenting on using iPSC-CMs to test splicing modulation therapies for HCM.
April 2 will be our next monthly online junior meeting presented by MDC PhD student Pragati Parakkat and CU Boulder PhD student Dakota Hunt. Pragati will be presenting on Titin N2B deficient EHTs as a tool to dissect titin mechanics and Dakota will be discussing alternative splicing in the Burmese python post-feeding response.
Our monthly online junior meeting on March 5th will be presented by MDC PhD student Timothy Tse on the characterization of Titin splice factors and by EMBL post-doc Kai Fenzl on high-throughput variant effect mapping via single-cardiomyocyte phenotyping.
Our first network meeting of 2025 will be May 19-21 in Boulder, Colorado. Please mark your calendars!
On February 6th, we will hear from presenters Adelya Gabdulkhakova (PhD student at the UK Heidelberg, Meder lab) and Stefan Meinke (Postdoc at MDC Berlin, Gotthardt lab). Adelya will be discussing the role of eccDNA in DCM and Stefan will be discussing cardiac alternative splicing regulation.
On December 5th, we will have presenters Liliia Demianenko and Jacobo Lopez Carballo participating in our monthly junior meeting. Both are PhD students in the Berlin Gotthardt lab. Liliia will present on the titin splice regulatory network and Jacobo will present on mRNA isoforms in scRNA-seq data, using RBM20 as an example.
Our monthly online junior meeting on November 7th will be presented by Linda Müller (EMBL) discussing the impact of RBM20 variants on mitochondria in cardiomyocytes and Pedro Prudêncio (iMM Lisbon) discussing natural antisense transcription in the Titin locus.
Our mid-term meeting will be held in Berlin May 28-31, 2024
The following network meeting will be held at Convento da Arrábida, Portugal November 12-15, 2024
On October 19 at 17:00 (CET) we will meet online for an in-depth presentation and discussion on iPSC-CM versus human heart led by senior member Carmo Fonseca.
Date:
| Presenter 1
| Presenter 2
|
November 7, 2023
| Linda Müller, EMBL (Steinmetz Lab)
| Pedro Prudêncio, iMM (Fonseca Lab)
|
December 5, 2023
| Liliia Demianenko, MDC (Gotthardt Lab)
| Jacobo Lopez Carballo, MDC (Gotthardt Lab)
|
January 2, 2024
|
|
|
February 6, 2024
| Adelya Gabdulkhakova, UK Heidelberg (Meder Lab)
| Stefan Meinke, MDC (Gotthardt Lab)
|
March 5, 2024
| Timothy Pok Man Tse, MDC (Gotthardt Lab)
| Kai Fenzl, EMBL (Steinmetz Lab)
|
April 2, 2024
| Pragati Parakkat, MDC (Gotthardt Lab)
| Dakota Hunt, CU Boulder (Leinwand Lab)
|
May 7, 2024
| Thomas Martin, CU Boulder (Leinwand Lab)
| TBD
|
Our second in-person network meeting took place on August 30th and 31st following the “The conceptual Power of Single Cell Biology” Elsevier conference. 16 PIs, scientists and students from all 6 CASTT labs met in beautiful San Diego for a program packed with scientific updates, mentoring, productive discussions on the discussion of iPSC-CM as a model system, isoform level data analysis, the regulation of cardiac splicing, and therapeutic targets. There were also plenty of chances for lively interactions over good food. All in all, a very successful meeting - looking forward to the next one in Berlin, Germany next May!
At our next CASTT Junior Online Meeting on August 1st, we'll have Maryam Aghadi (MDC Berlin) and Dominik Lindenhofer (EMBL) presenting some of their work on hypoxia-induced splice network alterations in cardiomyocytes and multiomic scDNA-scRNA technology to characterize non-coding variants.
This month's presenters for the CASTT Junior Meeting series are Bruna Gomes (Stanford) and Yuxiao Tan (CU Boulder). They will present their work on leveraging the power of deep learning in human genomics and promoting cardiomyocytes binucleation in the overfed Burmese python.
Next in the CASTT Junior Meeting series are Anastasiia Korosteleva (EMBL Heidelberg) and Beatriz Silva (iMM Lisbon), which will present their work on gene editing in dilated cardiomyopathy and on differences in cardiac splicing regulation in vivo vs in vitro.
In our April CASTT Junior Meeting we will have two talks by Marta Furtado (iMM Lisbon) and Timothy Tse (MDC Berlin) covering their work on MYBPC3 mutations in HCM and on methods to establish a cardiac splice regulatory network.
On March 20th we had our 3rd CASTT Meeting, were we evaluated our progress and efforts in 2022 and discussed our goals for 2023.
At our next CASTT Junior Online Meeting on March 7th we'll have Qianru Wang and Yuta Yamamoto, both from Stanford University, presenting some of their work on single-cell phenotyping and variant effect mapping in genetic cardiomyopathies.
© AG Gotthardt
At our next CASTT Junior Online Meeting on February 7th we'll have Linda Müller (EMBL Heidelberg) and Sarah Schudy (Heidelberg University) presenting some of their work on DCM-causing genetic variants and long-read sequencing of cardiomyopathy patients.
© AG Gotthardt
On December 6th we will have our first Junior Online Meeting, which will regularly take place on the first Tuesday of the month. This time we will hear about the ongoing work of Liliia, Dakota and Pragati.
© Gotthardt-Lab
Our first on-site meeting was a success! PIs, scientists and students from all CASTT labs met in Berlin for a fruitful day with great discussions on latest results and next efforts to strengthen collaboration.
Please save the date for our first in-person meeting in Berlin (June 16th, 2022), as a satellite event to the XXIV World Congress International Society for Heart Research (ISHR). We will meet at the Berlin Institute for Medical Systems Biology (BIMSB) in Berlin Mitte.
BIMSB is a part of MDC and located in Berlin-Mitte.
Our first official online meeting took place in March 18th, thank you all for the great discussion! Exciting starting point and looking forward to switching to in-person interactions during the ISHR World Congress in Berlin.
