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Methylation of cytosines is a prototypic epigenetic modification of the DNA. It has been implicated in various regulatory mechanisms across the animal kingdom and particularly in vertebrates. We mapped DNA methylation in 580 animal species (535 vertebrates, 45 invertebrates), resulting in 2443 genome-scale DNA methylation profiles of multiple organs. Bioinformatic analysis of this large dataset quantified the association of DNA methylation with the underlying genomic DNA sequence throughout vertebrate evolution. We observed a broadly conserved link with two major transitions—once in the first vertebrates and again with the emergence of reptiles. Cross-species comparisons focusing on individual organs supported a deeply conserved association of DNA methylation with tissue type, and cross-mapping analysis of DNA methylation at gene promoters revealed evolutionary changes for orthologous genes. In summary, this study establishes a large resource of vertebrate and invertebrate DNA methylomes, it showcases the power of reference-free epigenome analysis in species for which no reference genomes are available, and it contributes an epigenetic perspective to the study of vertebrate evolution.

Neutrophils are evolutionarily conserved innate immune cells playing pivotal roles in host defense. Zebrafish models have contributed substantially to our understanding of neutrophil functions but similarities to human neutrophil maturation have not been systematically characterized, which limits their applicability to studying human disease. Here we show, by generating and analysing transgenic zebrafish strains representing distinct neutrophil differentiation stages, a high-resolution transcriptional profile of neutrophil maturation. We link gene expression at each stage to characteristic transcription factors, including C/ebp-β, which is important for late neutrophil maturation. Cross-species comparison of zebrafish, mouse, and human samples confirms high molecular similarity of immature stages and discriminates zebrafish-specific from pan-species gene signatures. Applying the pan-species neutrophil maturation signature to RNA-sequencing data from human neuroblastoma patients reveals association between metastatic tumor cell infiltration in the bone marrow and an overall increase in mature neutrophils. Our detailed neutrophil maturation atlas thus provides a valuable resource for studying neutrophil function at different stages across species in health and disease. Maturation of innate immune cells is a graded stereotypic process which is often conserved across species. Here authors label distinct neutrophil leukocyte developmental stages via generating combinations of transgenic zebrafish reporter strains, followed by transcriptome analysis of different neutrophil maturation stages and comparison to the gene expression profile of developing neutrophils from humans and mice.

During the aging process, cells can enter cellular senescence, a state in which cells leave the cell cycle but remain viable. This mechanism is thought to protect tissues from propagation of damaged cells and the number of senescent cells has been shown to increase with age. The speed of aging determines the lifespan of a species and it varies significantly in different species. To assess the progress of cellular senescence during lifetime, we performed a comparative longitudinal study using histochemical detection of the senescence-associated beta-galactosidase as senescence marker to map the staining patterns in organs of the long-lived zebrafish and the short-lived turquoise killifish using light- and electron microscopy. We compared age stages corresponding to human stages of newborn, childhood, adolescence, adult and old age. We found tissue-specific but conserved signal patterns with respect to organ distribution. However, we found dramatic differences in the onset of tissue staining. The stained zebrafish organs show little to no signal at newborn age followed by a gradual increase in signal intensity, whereas the organs of the short-lived killifish show an early onset of staining already at newborn stage, which remains conspicuous at all age stages. The most prominent signal was found in liver, intestine, kidney and heart, with the latter showing the most prominent interspecies divergence in onset of staining and in staining intensity. In addition, we found staining predominantly in epithelial cells, some of which are post-mitotic, such as the intestinal epithelial lining. We hypothesize that the association of the strong and early-onset signal pattern in the short-lived killifish is consistent with a protective mechanism in a fast growing species. Furthermore, we believe that staining in post-mitotic cells may play a role in maintaining tissue integrity, suggesting different roles for cellular senescence during life.

Inflammation is a driving force of tendinopathy. The oxidation of phospholipids by free radicals is a consequence of inflammatory reactions and is an important indicator of tissue damage. Here, we have studied the impact of oxidized phospholipids (OxPAPC) on the function of human tenocytes. We observed that treatment with OxPAPC did not alter the morphology, growth and capacity to produce collagen in healthy or diseased tenocytes. However, since OxPAPC is a known modulator of the function of immune cells, we analyzed whether OxPAPC-treated immune cells might influence the fate of tenocytes. Co-culture of tenocytes with immature, monocyte-derived dendritic cells treated with OxPAPC (Ox-DCs) was found to enhance the proliferation of tenocytes, particularly those from diseased tendons. Using transcriptional profiling of Ox-DCs, we identified amphiregulin (AREG), a ligand for EGFR, as a possible mediator of this proliferation enhancing effect, which we could confirm using recombinant AREG. Of note, diseased tenocytes were found to express higher levels of EGFR compared to tenocytes isolated from healthy donors and show a stronger proliferative response upon co-culture with Ox-DCs, as well as AREG treatment. In summary, we identify an AREG-EGFR axis as a mediator of a DC-tenocyte crosstalk, leading to increased tenocyte proliferation and possibly tendon regeneration.

Human rhinoviruses (HRV) are the major cause of the common cold, one of the most frequent infectious diseases in humans. Though HRV infections of the upper respiratory tract are usually rather harmless, there is increasing evidence that HRV sets the stage for more dangerous pathogens, elicits asthmatic exacerbations, severe diseases in the lower respiratory tract and even autoimmunity. The pathogenic mechanisms of HRV infections leading to such complications are still poorly understood. It is a common strategy of pathogens to manipulate our immune system in order to evade an efficient immune response. A major characteristic of HRV is a high degree of species specificity. Thus, analyzing the potential immune evasion mechanisms used by HRV will be helpful for a better understanding of the pathogenesis of the common cold and may contribute to a better understanding of the human immune system as well. In this review we want to illuminate what is known about potential immune escape mechanisms used by HRV and discuss how such disturbances might lead to a suppressed and dysregulated immune competence in man.

Neutrophils are evolutionarily conserved innate defense cells implicated in diverse pathological processes. Zebrafish models have contributed substantially to our understanding of neutrophil functions, but similarities to human neutrophil maturation have not been characterized limiting applicability to study human disease. We generated transgenic zebrafish strains to distinguish neutrophil maturation grades in vivo and established a high-resolution transcriptional profile of neutrophil maturation. We linked gene expression at each stage to characteristic transcription factors, including C/ebp-beta important for late neutrophil maturation. Cross-species comparison of zebrafish, mouse, and human confirmed high molecular similarity in immature stages and discriminated zebrafish-specific from pan-species gene signatures. Applying pan-species neutrophil maturation signatures in RNA-seq data from neuroblastoma patients revealed an association of metastatic tumor cell infiltration in the bone marrow with an increase in mature neutrophils. Our detailed neutrophil maturation atlas provides a valuable resource for studying neutrophil function at different stages across species in health and disease.Competing Interest StatementThe authors have declared no competing interest.

Methylation of cytosines is the prototypic epigenetic modification of the DNA. It has been implicated in various regulatory mechanisms throughout the animal kingdom and particularly in vertebrates. We mapped DNA methylation in 580 animal species (535 vertebrates, 45 invertebrates), resulting in 2443 genome-scale, base-resolution DNA methylation profiles of primary tissue samples from various organs. Reference-genome independent analysis of this comprehensive dataset quantified the association of DNA methylation with the underlying genomic DNA sequence throughout vertebrate evolution. We observed a broadly conserved link with two major transitions – once in the first vertebrates and again with the emergence of reptiles. Cross-species comparisons focusing on individual organs supported a deeply conserved association of DNA methylation with tissue type, and cross-mapping analysis of DNA methylation at gene promoters revealed evolutionary changes for orthologous genes with conserved DNA methylation patterns. In summary, this study establishes a large resource of vertebrate and invertebrate DNA methylomes, it showcases the power of reference-free epigenome analysis in species for which no reference genomes are available, and it contributes an epigenetic perspective to the study of vertebrate evolution.

Briefly before the first peak of the COVID-19 pandemic in Berlin, Germany, schools closed in mid-March 2020. Following re-opening, schools resumed operation at a reduced level for nine weeks. During this phase, we aimed at assessing, among students and teachers, infection status, symptoms, individual behaviour, and institutional infection prevention measures. Twenty-four primary and secondary school classes, randomly selected across Berlin, were examined. Oro-nasopharyngeal swabs and capillary blood samples were collected to determine SARS-CoV-2 infection (PCR) and specific IgG (ELISA), respectively. Medical history, household characteristics, leisure activities, fear of infection, risk perception, hand hygiene, facemask wearing, and institutional preventive measures were assessed. Descriptive analysis was performed. Among 535 participants (385 students, 150 staff), one teenager was found to be infected with SARS-CoV-2 (0.2%), and seven individuals exhibited specific IgG (1.3%). Compared to pre-pandemic times, screen time (e.g., TV, gaming, social media) increased, and the majority of primary school students reported reduced physical activity (42.2%). Fear of infection and risk perception were relatively low, acceptance of adapted health behaviors was high. In this post-lockdown period of low SARS-CoV-2 incidence in Berlin, individual and school-level infection prevention measures were largely adhered to. Nevertheless, vigilance and continued preventive measures are essential to cope with future pandemic activity.