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... Show moreBackground 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. Show less
Two pandemics of respiratory distress diseases associated with zoonotic introductions of the species Severe acute respiratory syndrome-related coronavirus in the human population during 21st... Show moreTwo pandemics of respiratory distress diseases associated with zoonotic introductions of the species Severe acute respiratory syndrome-related coronavirus in the human population during 21st century raised unprecedented interest in coronavirus research and assigned it unseen urgency. The two viruses responsible for the outbreaks, SARS-CoV and SARS-CoV-2, respectively, are in the spotlight, and SARSCoV-2 is the focus of the current fast-paced research. Its foundation was laid down by studies of many coronaand related viruses that collectively form the vast order Nidovirales. Comparative genomics of nidoviruses played a key role in this advancement over more than 30 years. It facilitated the transfer of knowledge from characterized to newly identified viruses, including SARS-CoV and SARS-CoV-2, as well as contributed to the dissection of the nidovirus proteome and identification of patterns of variations between different taxonomic groups, from species to families. This review revisits selected cases of protein conservation and variation that define nidoviruses, illustrates the remarkable plasticity of the proteome during nidovirus adaptation, and asks questions at the interface of the proteome and processes that are vital for nidovirus reproduction and could inform the ongoing research of SARS-CoV-2.(c) 2020 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). Show less
The order Nidovirales, including families Coronaviridae and Arteriviridae, is a monophyletic group of highly divergent (+)ssRNA viruses that infect vertebrate and invertebrate hosts; they share... Show moreThe order Nidovirales, including families Coronaviridae and Arteriviridae, is a monophyletic group of highly divergent (+)ssRNA viruses that infect vertebrate and invertebrate hosts; they share conserved genome organization and replication mechanisms. The genome sequence is the only information available about many newly discovered nidoviruses whose number is fast increasing driven by technology advancements. This development makes comparative genomics, an approach that already has been used extensively in nidovirology, increasingly important. In this thesis, diverse methods of comparative genomics were used to address scientific questions about composition and evolution of the nidovirus genome and proteome, and their connection to the biology of nidoviruses. Three studies were conducted in collaboration with experimental researchers, and ranged from the analysis of the highly divergent polyprotein N-terminus in arteriviruses, to identification of the fifth universally conserved domain of nidoviruses, and to characterization of a nidovirus with the largest known RNA genome. The latter study prompted the development of a bioinformatics tool facilitating functional annotation of large multidomain polyproteins. The thesis illustrates how a notion of nidovirus-specific conservation has been steadily refined as a result of recent discoveries. Show less
