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Autoimmune diseases, such as psoriasis and arthritis, show a patchy distribution of inflammation despite systemic dysregulation of adaptive immunity. Thus, additional tissue-derived signals, such as danger-associated molecular patterns (DAMPs), are indispensable for manifestation of local inflammation. S100A8/S100A9 complexes are the most abundant DAMPs in many autoimmune diseases. However, regulatory mechanisms locally restricting DAMP activities are barely understood. We now unravel for the first time, to our knowledge, a mechanism of autoinhibition in mice and humans restricting S100-DAMP activity to local sites of inflammation. Combining protease degradation, pull-down assays, mass spectrometry, and targeted mutations, we identified specific peptide sequences within the second calcium-binding EF-hands triggering TLR4/MD2-dependent inflammation. These binding sites are free when S100A8/S100A9 heterodimers are released at sites of inflammation. Subsequently, S100A8/S100A9 activities are locally restricted by calcium-induced (S100A8/S100A9)2 tetramer formation hiding the TLR4/MD2-binding site within the tetramer interphase, thus preventing undesirable systemic effects. Loss of this autoinhibitory mechanism in vivo results in TNF-α-driven fatal inflammation, as shown by lack of tetramer formation in crossing S100A9-/- mice with 2 independent TNF-α-transgene mouse strains. Since S100A8/S100A9 is the most abundant DAMP in many inflammatory diseases, specifically blocking the TLR4-binding site of active S100 dimers may represent a promising approach for local suppression of inflammatory diseases, avoiding systemic side effects.

Cardiovascular diseases (CVDs) are of multifactorial origin and can be attributed to several genetic and environmental components. CVDs are the leading cause of mortality worldwide and they primarily damage the heart and the vascular system. Non-coding RNA (ncRNA) refers to functional RNA molecules, which have been transcribed into DNA but do not further get translated into proteins. Recent transcriptomic studies have identified the presence of thousands of ncRNA molecules across species. In humans, less than 2% of the total genome represents the protein-coding genes. While the role of many ncRNAs is yet to be ascertained, some long non-coding RNAs (lncRNAs) and microRNAs (miRNAs) have been associated with disease progression, serving as useful diagnostic and prognostic biomarkers. A plethora of data repositories specialized in ncRNAs have been developed over the years using publicly available high-throughput data from next-generation sequencing and other approaches, that cover various facets of ncRNA research like basic and functional annotation, expressional profile, structural and molecular changes, and interaction with other biomolecules. Here, we provide a compendium of the current ncRNA databases relevant to cardiovascular research.

Treatment of hypertension-mediated cardiac damage with left ventricular (LV) hypertrophy (LVH) and heart failure remains challenging. To identify novel targets, we performed comparative transcriptome analysis between genetic models derived from stroke-prone spontaneously hypertensive rats (SHRSP). Here, we identified carboxypeptidase X 2 (Cpxm2) as a genetic locus affecting LV mass. Analysis of isolated rat cardiomyocytes and cardiofibroblasts indicated Cpxm2 expression and intrinsic upregulation in genetic hypertension. Immunostaining indicated that CPXM2 associates with the t-tubule network of cardiomyocytes. The functional role of Cpxm2 was further investigated in Cpxm2-deficient (KO) and wild-type (WT) mice exposed to deoxycorticosterone acetate (DOCA). WT and KO animals developed severe and similar systolic hypertension in response to DOCA. WT mice developed severe LV damage, including increases in LV masses and diameters, impairment of LV systolic and diastolic function and reduced ejection fraction. These changes were significantly ameliorated or even normalized (i.e., ejection fraction) in KO-DOCA animals. LV transcriptome analysis showed a molecular cardiac hypertrophy/remodeling signature in WT but not KO mice with significant upregulation of 1234 transcripts, including Cpxm2, in response to DOCA. Analysis of endomyocardial biopsies from patients with cardiac hypertrophy indicated significant upregulation of CPXM2 expression. These data support further translational investigation of CPXM2.

Genomic instability, the unresolved accumulation of DNA variants, is hypothesized as one of the contributors to the natural aging process. We assessed the frequency of unresolved DNA damage reaching the transcriptome of the murine myocardium during the course of natural aging and in hearts from four distinct mouse models of premature aging with established aging-related cardiac dysfunctions. RNA sequencing and variant calling based on total RNA sequencing was compared between hearts from naturally aging mice, mice with cardiomyocyte-specific deficiency of Ercc1, a component of the DNA repair machinery, mice with reduced mitochondrial antioxidant capacity, Tert-deficient mice with reduced telomere length, and a mouse model of human Hutchinson–Gilford progeria syndrome (HGPS). Our results demonstrate that no enrichment in variants is evident in the naturally aging murine hearts until 2 y of age from the HGPS mouse model or mice with reduced telomere lengths. In contrast, a dramatic accumulation of variants was evident in Ercc1 cardiomyocyte-specific knockout mice with deficient DNA repair machinery, in mice with reduced mitochondrial antioxidant capacity, and in the intestine, liver, and lung of naturally aging mice. Our data demonstrate that genomic instability does not evidently contribute to naturally aging of the mouse heart in contrast to other organs and support the contention that the endogenous DNA repair machinery is remarkably active to maintain genomic integrity in cardiac cells throughout life.

The patterns of genomic divergence during ecological speciation are shaped by a combination of evolutionary forces. Processes such as genetic drift, local reduction of gene flow around genes causing reproductive isolation, hitchhiking around selected variants, variation in recombination and mutation rates are all factors that can contribute to the heterogeneity of genomic divergence. On the basis of 60 fully sequenced three-spined stickleback genomes, we explore these different mechanisms explaining the heterogeneity of genomic divergence across five parapatric lake and river population pairs varying in their degree of genetic differentiation. We find that divergent regions of the genome are mostly specific for each population pair, while their size and abundance are not correlated with the extent of genome-wide population differentiation. In each pair-wise comparison, an analysis of allele frequency spectra reveals that 25-55% of the divergent regions are consistent with a local restriction of gene flow. Another large proportion of divergent regions (38-75%) appears to be mainly shaped by hitchhiking effects around positively selected variants. We provide empirical evidence that alternative mechanisms determining the evolution of genomic patterns of divergence are not mutually exclusive, but rather act in concert to shape the genome during population differentiation, a first necessary step towards ecological speciation.

To bridge the current gap between the known mechanisms of atrial fibrillation (AF) and the clinical management of patients with this arrhythmia, Fabritz and colleagues propose a roadmap to develop a set of clinical markers that reflect the major causes of AF in patients. A new, mechanism-based classification of AF can provide the basis for personalized prevention and management. Despite remarkable advances in antiarrhythmic drugs, ablation procedures, and stroke-prevention strategies, atrial fibrillation (AF) remains an important cause of death and disability in middle-aged and elderly individuals. Unstructured management of patients with AF sharply contrasts with our detailed, although incomplete, knowledge of the mechanisms that cause AF and its complications. Altered calcium homeostasis, atrial fibrosis and ageing, ion-channel dysfunction, autonomic imbalance, fat-cell infiltration, and oxidative stress, in addition to a susceptible genetic background, contribute to the promotion, maintenance, and progression of AF. However, clinical management of patients with AF is currently guided by stroke risk parameters, AF pattern, and symptoms. In response to this apparent disconnect between the known pathophysiology of AF and clinical management, we propose a roadmap to develop a set of clinical markers that reflect the major causes of AF in patients. Thereby, the insights into the mechanisms causing AF will be transformed into a format that can underpin future personalized strategies to prevent and treat AF, ultimately informing better patient care.

We present a comprehensive toolkit for post-processing, visualization and advanced analysis of GWAS results. In the spirit of comparable tools for gene-expression analysis, we attempt to unify and simplify several procedures that are essential for the interpretation of GWAS results. This includes the generation of advanced Manhattan and regional association plots including rare variant display as well as novel interaction network analysis tools for the investigation of systems-biology aspects. Our package supports virtually all model organisms and represents the first cohesive implementation of such tools for the popular language R. Previous software of that range is dispersed over a wide range of platforms and mostly not adaptable for custom work pipelines. We demonstrate the utility of this package by providing an example workflow on a publicly available dataset.

Coronary artery disease (CAD) is a long-lasting inflammatory disease characterized by monocyte migration into the vessel wall leading to clinical events like myocardial infarction (MI). However, the role of monocyte subsets, especially their miRNA-driven differentiation in this scenario is still in its infancy. Here, we characterized monocyte subsets in controls and disease phenotypes of CAD and MI patients using flow cytometry and miRNA and mRNA expression profiling using RNA sequencing. We observed major differences in the miRNA profiles between the classical (CD14 ++ CD16 − ) and nonclassical (CD14 + CD16 ++ ) monocyte subsets irrespective of the disease phenotype suggesting the Cyclin-dependent Kinase 6 (CDK6) to be an important player in monocyte maturation. Between control and MI patients, we found a set of miRNAs to be differentially expressed in the nonclassical monocytes and targeting CCND2 (Cyclin D2) that is able to enhance myocardial repair. Interestingly, miRNAs as miR-125b playing a role in vascular calcification were differentially expressed in the classical subset in patients suffering from CAD and not MI in comparison to control samples. In conclusion, our study describes specific peculiarities of monocyte subset miRNA expression in control and diseased samples and provides basis to further functional analysis and to identify new cardiovascular disease treatment targets.

The proinflammatory alarmins S100A8 and S100A9 are among the most abundant proteins in neutrophils and monocytes but are completely silenced after differentiation to macrophages. The molecular mechanisms of the extraordinarily dynamic transcriptional regulation of S100a8 and S100a9 genes, however, are only barely understood. Using an unbiased genome-wide CRISPR/Cas9 knockout (KO)-based screening approach in immortalized murine monocytes, we identified the transcription factor C/EBPδ as a central regulator of S100a8 and S100a9 expression. We showed that S100A8/A9 expression and thereby neutrophil recruitment and cytokine release were decreased in C/EBPδ KO mice in a mouse model of acute lung inflammation. S100a8 and S100a9 expression was further controlled by the C/EBPδ antagonists ATF3 and FBXW7. We confirmed the clinical relevance of this regulatory network in subpopulations of human monocytes in a clinical cohort of cardiovascular patients. Moreover, we identified specific C/EBPδ-binding sites within S100a8 and S100a9 promoter regions, and demonstrated that C/EBPδ-dependent JMJD3-mediated demethylation of H3K27me 3 is indispensable for their expression. Overall, our work uncovered C/EBPδ as a novel regulator of S100a8 and S100a9 expression. Therefore, C/EBPδ represents a promising target for modulation of inflammatory conditions that are characterized by S100a8 and S100a9 overexpression.

We recently reported a family-based genome wide association study (GWAS) for pediatric stroke pointing our attention to two significantly associated genes of the ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs) gene family ADAMTS2 (rs469568, p = 8x10.sup.-6) and ADAMTS12 (rs1364044, p = 2.9x10.sup.-6). To further investigate these candidate genes, we applied a targeted resequencing approach on 48 discordant sib-pairs for pediatric stroke followed by genotyping of the detected non-synonymous variants in the full cohort of 270 offspring trios and subsequent fine mapping analysis. We identified eight non-synonymous SNPs in ADAMTS2 and six in ADAMTS12 potentially influencing the respective protein function. These variants were genotyped within a cohort of 270 affected offspring trios, association analysis revealed the ADAMTS12 variant rs77581578 to be significantly under-transmitted (p = 6.26x10.sup.-3) to pediatric stroke patients. The finding was validated in a pediatric venous thromboembolism (VTE) cohort of 189 affected trios. Subsequent haplotype analysis of ADAMTS12 detected a significantly associated haplotype comprising the originally identified GWAS variant. Several ADAMTS genes such as ADAMTS13 are involved in thromboembolic disease process. Here, we provide further evidence for ADAMTS12 to likely play a role in pediatric stroke. Further functional studies are warranted to assess the functional role of ADAMTS12 in the pathogenesis of stroke.