👤 Bastiaan J Boukens

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. 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. 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. Show less

Genome-wide association studies previously identified an association of rs9388451 at chromosome 6q22.3 (near We used an integrative approach entailing transcriptomic studies in human hearts and electrophysiological studies in We queried expression quantitative trait locus data acquired in 190 human left ventricular samples from the genotype-tissue expression consortium for This study uncovers a role of Show less

Brugada syndrome is a rare cardiac arrhythmia disorder, causally related to SCN5A mutations in around 20% of cases. Through a genome-wide association study of 312 individuals with Brugada syndrome and 1,115 controls, we detected 2 significant association signals at the SCN10A locus (rs10428132) and near the HEY2 gene (rs9388451). Independent replication confirmed both signals (meta-analyses: rs10428132, P = 1.0 × 10(-68); rs9388451, P = 5.1 × 10(-17)) and identified one additional signal in SCN5A (at 3p21; rs11708996, P = 1.0 × 10(-14)). The cumulative effect of the three loci on disease susceptibility was unexpectedly large (Ptrend = 6.1 × 10(-81)). The association signals at SCN5A-SCN10A demonstrate that genetic polymorphisms modulating cardiac conduction can also influence susceptibility to cardiac arrhythmia. The implication of association with HEY2, supported by new evidence that Hey2 regulates cardiac electrical activity, shows that Brugada syndrome may originate from altered transcriptional programming during cardiac development. Altogether, our findings indicate that common genetic variation can have a strong impact on the predisposition to rare diseases. Show less

In patients with Brugada syndrome, arrhythmias typically originate in the right ventricular outflow tract (RVOT). The RVOT develops from the slowly conducting embryonic outflow tract. We hypothesize that this embryonic phenotype is maintained in the fetal and adult RVOT and leads to conduction slowing, especially after sodium current reduction. We determined expression patterns in the embryonic myocardium and performed activation mapping in fetal and adult hearts, including hearts from adult mice heterozygous for a mutation associated with Brugada syndrome (Scn5a1798insD/+). The embryonic RVOT was characterized by expression of Tbx2, a repressor of differentiation, and absence of expression of both Hey2, a ventricular transcription factor, and Gja1, encoding the principal gap-junction subunit for ventricular fast conduction. Also, conduction velocity was lower in the RVOT than in the right ventricular free wall. Later in the development, Gja1 and Scn5a expression remained lower in the subepicardial myocardium of the RVOT than in RV myocardium. Nevertheless, conduction velocity in the adult RVOT was similar to that of the right ventricular free wall. However, in hearts of Scn5a1798insD/+ mice and in normal hearts treated with ajmaline, conduction was slower in the RVOT than in the right ventricular wall. The slowly conducting embryonic phenotype is maintained in the fetal and adult RVOT and is unmasked when cardiac sodium channel function is reduced. Show less