Functional diversification of Argonautes in nematodes:an expanding universe

In the last decade, many diverse RNAi (RNA interference) pathways have been discovered that mediate gene silencing at epigenetic, transcriptional and post-transcriptional levels. The diversity of RNAi pathways is inherently linked to the evolution of Ago (Argonaute) proteins, the central protein component of RISCs (RNA-induced silencing complexes). An increasing number of diverse Agos have been identified in different species. The functions of most of these proteins are not yet known, but they are generally assumed to play roles in development, genome stability and/or protection against viruses. Recent research in the nematode Caenorhabditis elegans has expanded the breadth of RNAi functions to include transgenerational epigenetic memory and, possibly, environmental sensing. These functions are inherently linked to the production of secondary siRNAs (small interfering RNAs) that bind to members of a clade of WAGOs (worm-specific Agos). In the present article, we review briefly what is known about the evolution and function of Ago proteins in eukaryotes, including the expansion of WAGOs in nematodes. We postulate that the rapid evolution of WAGOs enables the exceptional functional plasticity of nematodes, including their capacity for parasitism

Silencing of germline-expressed genes by DNA elimination in somatic cells

SummaryChromatin diminution is the programmed elimination of specific DNA sequences during development. It occurs in diverse species, but the function(s) of diminution and the specificity of sequence loss remain largely unknown. Diminution in the nematode Ascaris suum occurs during early embryonic cleavages and leads to the loss of germline genome sequences and the formation of a distinct genome in somatic cells. We found that ∼43 Mb (∼13%) of genome sequence is eliminated in A. suum somatic cells, including ∼12.7 Mb of unique sequence. The eliminated sequences and location of the DNA breaks are the same in all somatic lineages from a single individual and between different individuals. At least 685 genes are eliminated. These genes are preferentially expressed in the germline and during early embryogenesis. We propose that diminution is a mechanism of germline gene regulation that specifically removes a large number of genes involved in gametogenesis and early embryogenesis

piRNAs Can Trigger a Multigenerational Epigenetic Memory in the Germline of C. elegans

SummaryTransgenerational effects have wide-ranging implications for human health, biological adaptation, and evolution; however, their mechanisms and biology remain poorly understood. Here, we demonstrate that a germline nuclear small RNA/chromatin pathway can maintain stable inheritance for many generations when triggered by a piRNA-dependent foreign RNA response in C.elegans. Using forward genetic screens and candidate approaches, we find that a core set of nuclear RNAi and chromatin factors is required for multigenerational inheritance of environmental RNAi and piRNA silencing. These include a germline-specific nuclear Argonaute HRDE1/WAGO-9, a HP1 ortholog HPL-2, and two putative histone methyltransferases, SET-25 and SET-32. piRNAs can trigger highly stable long-term silencing lasting at least 20 generations. Once established, this long-term memory becomes independent of the piRNA trigger but remains dependent on the nuclear RNAi/chromatin pathway. Our data present a multigenerational epigenetic inheritance mechanism induced by piRNAs.Graphical AbstractHighlights► Multigenerational inheritance and piRNAs converge on same nuclear silencing pathway ► HRDE1/WAGO-9 and chromatin factors required for inheritance of piRNA silencing ► piRNAs can induce multigenerational silencing for more than 20 generations. ► Long-term memory independent of piRNA triggers but remains dependent on nuclear pathwayMultigenerational inheritance and piRNAs converge on same silencing pathway, in which both nuclear WAGOs and chromatin factors are required. The piRNA trigger can be lost, but the nuclear silencing pathway maintains the silencing for more than 20 generations

Gender differences in associations of depressive symptoms and anxiety with inflammatory markers in patients with non-obstructive coronary artery disease

Objective The aim of this study was to examine gender differences of the associations between depressive symptoms and anxiety with inflammatory markers in patients with non-obstructive coronary artery disease (NOCAD). Methods Depressive symptoms and anxiety (Beck Depression Inventory BDI and Hospital Anxiety and Depression Scale HADS) were examined in 524 patients with NOCAD (52% women, mean age 64 ± 9 years) as part of the TweeSteden Mild Stenosis (TWIST) observational cohort study. Blood samples were analyzed for neutrophil gelatinase-associated lipocalin (NGAL) levels, high-sensitive C-reactive protein (hsCRP), and leukocyte differentiation. Multivariate analysis for the inflammatory markers with main effects of depressive symptoms or anxiety, gender, and their interactions were observed. Results Women had elevated levels of hsCRP, and a lower monocyte and eosinophil count than men, with small to medium effect sizes (range η(p)2 = 0.019–0.047). After Holm-Bonferroni correction depressive symptoms according to the BDI were associated with an overall elevated hsCRP level explaining 2.4% of the hsCRP variance. A significant positive association between BDI cognitive symptoms with elevated hsCRP level was observed in men (R2 = 0.045), but not in women (R2 < 0.001). Adjustment for age, body mass index, smoking, and physical activity attenuated this finding. Conclusion Small associations of inflammatory markers with depressive symptoms and anxiety were confounded by lifestyle factors, predominantly smoking. The interacting roles of gender, smoking, and psychological factors on inflammatory markers may point toward different behavioral and inflammatory pathways for women and men with NOCAD, which remains to be further explored