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1. Multi-omics integration identifies key upstream regulators of pathomechanisms in hypertrophic cardiomyopathy due to truncating MYBPC3 mutations

Author

Pei, J., Schuldt, M., Nagyova, E., Gu, Z., el Bouhaddani, S., Yiangou, L., Jansen, M., Calis, J. J. A., Dorsch, L. M., Blok, C. Snijders, van den Dungen, N. A. M., Lansu, N., Boukens, B. J., Efimov, I. R., Michels, M., Verhaar, M. C., de Weger, R., Vink, A., van Steenbeek, F. G., Baas, A. F., Davis, R. P., Uh, H. W., Kuster, D. W. D., Cheng, C., Mokry, M., van der Velden, J., Asselbergs, F. W., and Harakalova, M.

Published
2021
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2. Multi-omics integration identifies key upstream regulators of pathomechanisms in hypertrophic cardiomyopathy due to truncating MYBPC3 mutations

Author

Pei, J, Schuldt, M, Nagyova, E, Gu, Z, El Bouhaddani, S, Yiangou, L, Jansen, M, Calis, J J A, Dorsch, L M, Blok, C Snijders, van den Dungen, N A M, Lansu, N, Boukens, B J, Efimov, I R, Michels, M, Verhaar, M C, de Weger, R, Vink, A, van Steenbeek, F G, Baas, A F, Davis, R P, Uh, H W, Kuster, D W D, Cheng, C, Mokry, M, van der Velden, J, Asselbergs, F W, Harakalova, M, Pei, J, Schuldt, M, Nagyova, E, Gu, Z, El Bouhaddani, S, Yiangou, L, Jansen, M, Calis, J J A, Dorsch, L M, Blok, C Snijders, van den Dungen, N A M, Lansu, N, Boukens, B J, Efimov, I R, Michels, M, Verhaar, M C, de Weger, R, Vink, A, van Steenbeek, F G, Baas, A F, Davis, R P, Uh, H W, Kuster, D W D, Cheng, C, Mokry, M, van der Velden, J, Asselbergs, F W, and Harakalova, M

Abstract

BACKGROUND: Hypertrophic cardiomyopathy (HCM) is the most common genetic disease of the cardiac muscle, frequently caused by mutations in MYBPC3. However, little is known about the upstream pathways and key regulators causing the disease. Therefore, we employed a multi-omics approach to study the pathomechanisms underlying HCM comparing patient hearts harboring MYBPC3 mutations to control hearts.RESULTS: Using H3K27ac ChIP-seq and RNA-seq we obtained 9310 differentially acetylated regions and 2033 differentially expressed genes, respectively, between 13 HCM and 10 control hearts. We obtained 441 differentially expressed proteins between 11 HCM and 8 control hearts using proteomics. By integrating multi-omics datasets, we identified a set of DNA regions and genes that differentiate HCM from control hearts and 53 protein-coding genes as the major contributors. This comprehensive analysis consistently points toward altered extracellular matrix formation, muscle contraction, and metabolism. Therefore, we studied enriched transcription factor (TF) binding motifs and identified 9 motif-encoded TFs, including KLF15, ETV4, AR, CLOCK, ETS2, GATA5, MEIS1, RXRA, and ZFX. Selected candidates were examined in stem cell-derived cardiomyocytes with and without mutated MYBPC3. Furthermore, we observed an abundance of acetylation signals and transcripts derived from cardiomyocytes compared to non-myocyte populations.CONCLUSIONS: By integrating histone acetylome, transcriptome, and proteome profiles, we identified major effector genes and protein networks that drive the pathological changes in HCM with mutated MYBPC3. Our work identifies 38 highly affected protein-coding genes as potential plasma HCM biomarkers and 9 TFs as potential upstream regulators of these pathomechanisms that may serve as possible therapeutic targets.

Published
2021

3. Multi-omics integration identifies key upstream regulators of pathomechanisms in hypertrophic cardiomyopathy due to truncating MYBPC3 mutations

Author

Afd Pharmacoepi & Clinical Pharmacology, Interne geneeskunde GD, dCSCA AVR, Sub Inorganic Chemistry and Catalysis, LS Vertaalwetenschap, CS_Genetics, Pei, J, Schuldt, M, Nagyova, E, Gu, Z, El Bouhaddani, S, Yiangou, L, Jansen, M, Calis, J J A, Dorsch, L M, Blok, C Snijders, van den Dungen, N A M, Lansu, N, Boukens, B J, Efimov, I R, Michels, M, Verhaar, M C, de Weger, R, Vink, A, van Steenbeek, F G, Baas, A F, Davis, R P, Uh, H W, Kuster, D W D, Cheng, C, Mokry, M, van der Velden, J, Asselbergs, F W, Harakalova, M, Afd Pharmacoepi & Clinical Pharmacology, Interne geneeskunde GD, dCSCA AVR, Sub Inorganic Chemistry and Catalysis, LS Vertaalwetenschap, CS_Genetics, Pei, J, Schuldt, M, Nagyova, E, Gu, Z, El Bouhaddani, S, Yiangou, L, Jansen, M, Calis, J J A, Dorsch, L M, Blok, C Snijders, van den Dungen, N A M, Lansu, N, Boukens, B J, Efimov, I R, Michels, M, Verhaar, M C, de Weger, R, Vink, A, van Steenbeek, F G, Baas, A F, Davis, R P, Uh, H W, Kuster, D W D, Cheng, C, Mokry, M, van der Velden, J, Asselbergs, F W, and Harakalova, M

Published
2021

4. Multi-omics integration identifies key upstream regulators of pathomechanisms in hypertrophic cardiomyopathy due to truncating MYBPC3 mutations

Author

Onderzoek Precision medicine, Other research (not in main researchprogram), Biostatistiek Onderzoek, Genetica Klinische Genetica, Immuno/reuma onderzoek 5 (Vastert2), CMM Groep Cuppen, Unit Opleiding Aios, Nefro Vasculaire Geneeskunde, Circulatory Health, Regenerative Medicine and Stem Cells, Pathologie Laboratorium diagnostiek, Pathologie Pathologen staf, JC onderzoeksprogramma Methodologie, Onderzoek, Child Health, Team Medisch, Pei, J, Schuldt, M, Nagyova, E, Gu, Z, El Bouhaddani, S, Yiangou, L, Jansen, M, Calis, J J A, Dorsch, L M, Blok, C Snijders, van den Dungen, N A M, Lansu, N, Boukens, B J, Efimov, I R, Michels, M, Verhaar, M C, de Weger, R, Vink, A, van Steenbeek, F G, Baas, A F, Davis, R P, Uh, H W, Kuster, D W D, Cheng, C, Mokry, M, van der Velden, J, Asselbergs, F W, Harakalova, M, Onderzoek Precision medicine, Other research (not in main researchprogram), Biostatistiek Onderzoek, Genetica Klinische Genetica, Immuno/reuma onderzoek 5 (Vastert2), CMM Groep Cuppen, Unit Opleiding Aios, Nefro Vasculaire Geneeskunde, Circulatory Health, Regenerative Medicine and Stem Cells, Pathologie Laboratorium diagnostiek, Pathologie Pathologen staf, JC onderzoeksprogramma Methodologie, Onderzoek, Child Health, Team Medisch, Pei, J, Schuldt, M, Nagyova, E, Gu, Z, El Bouhaddani, S, Yiangou, L, Jansen, M, Calis, J J A, Dorsch, L M, Blok, C Snijders, van den Dungen, N A M, Lansu, N, Boukens, B J, Efimov, I R, Michels, M, Verhaar, M C, de Weger, R, Vink, A, van Steenbeek, F G, Baas, A F, Davis, R P, Uh, H W, Kuster, D W D, Cheng, C, Mokry, M, van der Velden, J, Asselbergs, F W, and Harakalova, M

Published
2021

5. Increased cytokine response after toll-like receptor stimulation in patients with stable coronary artery disease.

Author

Elsenberg EH, Sels JE, Hillaert MA, Schoneveld AH, van den Dungen NA, van Holten TC, Roest M, Jukema JW, van Zonneveld AJ, de Groot PG, Pijls N, Pasterkamp G, and Hoefer IE

Subjects
Aged, Area Under Curve, Atherosclerosis, C-Reactive Protein metabolism, CD11b Antigen metabolism, Case-Control Studies, Cytokines blood, Female, Humans, Male, Middle Aged, Monocytes cytology, P-Selectin metabolism, Risk Factors, Angina, Stable blood, Coronary Artery Disease blood, Cytokines metabolism, Leukocytes cytology, Lipopolysaccharides blood, Toll-Like Receptors blood
Abstract

Objective: Atherosclerosis is associated with increased levels of plasma cytokines and expression of Toll-like receptors (TLRs). Yet, little is known about the potential use of TLR ligand induced cytokine release as a biomarker of coronary artery disease (CAD). In this study, we investigated whether TLR ligand induced cytokine release is associated with atherosclerotic disease severity and its predictive value for future cardiovascular events., Methods: Blood samples were obtained from 260 patients with stable angina and 15 healthy controls. Cytokine levels of TNFα, IL-8 and IL-6 were measured after 2 h of whole blood stimulation with 10 ng/ml lipopolysaccharide (LPS, TLR4 ligand) and P3C 500 ng/ml (TLR2 ligand). In a subgroup, dose-response curves were created using additional LPS concentrations., Results: LPS induced whole blood release of TNFα and IL-6, but not IL-8, was significantly higher in patients compared to healthy controls. Among CAD patients, TLR responses did hardly differ when associated with the presence of traditional risk factors and atherosclerotic disease severity (number of diseased vessels and coronary stenosis degree). Patients with secondary events during follow-up showed a trend towards an increased TLR response. Furthermore, positive associations were found between CRP levels and TLR-induced TNFα (CRP<2: 2055 pg/ml; CRP>2: 2364 pg/ml) and IL-6 production (CRP<2: 1742 pg/ml; CRP>2: 2250 pg/ml)., Conclusion: In conclusion, TLR-induced whole blood cytokine release in patients with stable angina indicates the presence of coronary atherosclerosis but does not reflect its severity., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

Published
2013
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