The chromatin remodeling factor ISW-1 integrates organismal responses against nuclear and mitochondrial stress

Age-associated changes in chromatin structure have a major impact on organismal longevity. Despite being a central part of the ageing process, the organismal responses to the changes in chromatin organization remain unclear. Here we show that moderate disturbance of histone balance during C. elegans development alters histone levels and triggers a stress response associated with increased expression of cytosolic small heat-shock proteins. This stress response is dependent on the transcription factor, HSF-1, and the chromatin remodeling factor, ISW-1. In addition, we show that mitochondrial stress during developmental stages also modulates histone levels, thereby activating a cytosolic stress response similar to that caused by changes in histone balance. These data indicate that histone and mitochondrial perturbations are both monitored through chromatin remodeling and involve the activation of a cytosolic response that affects organismal longevity. HSF-1 and ISW-1 hence emerge as a central mediator of this multi-compartment proteostatic response regulating longevity.Peer reviewe

Genetic, molecular and physiological basis of variation in Drosophila gut immunocompetence

Gut immunocompetence involves immune, stress and regenerative processes. To investigate the determinants underlying inter-individual variation in gut immunocompetence, we perform enteric infection of 140 Drosophila lines with the entomopathogenic bacterium Pseudomonas entomophila and observe extensive variation in survival. Using genome-wide association analysis, we identify several novel immune modulators. Transcriptional profiling further shows that the intestinal molecular state differs between resistant and susceptible lines, already before infection, with one transcriptional module involving genes linked to reactive oxygen species (ROS) metabolism contributing to this difference. This genetic and molecular variation is physiologically manifested in lower ROS activity, lower susceptibility to ROS-inducing agent, faster pathogen clearance and higher stem cell activity in resistant versus susceptible lines. This study provides novel insights into the determinants underlying population-level variability in gut immunocompetence, revealing how relatively minor, but systematic genetic and transcriptional variation can mediate overt physiological differences that determine enteric infection susceptibility

Transforming Growth Factor β/Activin Signaling Functions as a Sugar-Sensing Feedback Loop to Regulate Digestive Enzyme Expression

Summary: Organisms need to assess their nutritional state and adapt their digestive capacity to the demands for various nutrients. Modulation of digestive enzyme production represents a rational step to regulate nutriment uptake. However, the role of digestion in nutrient homeostasis has been largely neglected. In this study, we analyzed the mechanism underlying glucose repression of digestive enzymes in the adult Drosophila midgut. We demonstrate that glucose represses the expression of many carbohydrases and lipases. Our data reveal that the consumption of nutritious sugars stimulates the secretion of the transforming growth factor β (TGF-β) ligand, Dawdle, from the fat body. Dawdle then acts via circulation to activate TGF-β/Activin signaling in the midgut, culminating in the repression of digestive enzymes that are highly expressed during starvation. Thus, our study not only identifies a mechanism that couples sugar sensing with digestive enzyme expression but points to an important role of TGF-β/Activin signaling in sugar metabolism. : Organisms modulate their digestive processes to reflect their nutritional state. In this study, Chng et al. demonstrate that the TGF-β/Activin pathway functions as a carbohydrate-sensing mechanism in the adult Drosophila midgut to regulate digestive enzyme expression. They show that the TGF-β ligand, Dawdle, and the canonical TGF-β/Activin signaling are essential to couple carbohydrate sensing with digestive enzyme expression. Thus, their study highlights an unexpected function of TGF-β/Activin signaling that is beyond their established roles in development and immunity

Randomized codon mutagenesis reveals that the HIV Rev arginine-rich motif is robust to substitutions and that double substitution of two critical residues alters specificity

The binding of the arginine-rich motif (ARM) of HIV Rev protein to its high-affinity site in stem IIB in the Rev response element (RRE) initiates assembly of a ribonucleoprotein complex that mediates the export of essential, incompletely spliced viral transcripts. Many biochemical, genetic, and structural studies of RevRRE IIB have been published, yet the roles of many peptide residues in Rev ARM are unconfirmed by mutagenesis. Rev aptamer I (RAI) is an optimized RRE IIB that binds Rev with higher affinity and for which mutational data are sparse. Randomized-codon libraries of Rev ARM were assayed for their ability to bind RRE IIB and RAI using a bacterial reporter system based on bacteriophage N-nut antitermination. Most Rev ARM residues tolerated substitutions without strong loss of binding to RRE IIB, and all except arginine 39 tolerated substitution without strong loss of binding to RAI. The pattern of critical Rev residues is not the same for RRE IIB and RAI, suggesting important differences between the interactions. The results support and aid the interpretation of existing structural models. Observed clinical variation is consistent with additional constraints on Rev mutation. By chance, we found double mutants of two highly critical residues, arginine 35 (to glycine) and asparagine 40 (to valine or lysine), that bind RRE IIB well, but not RAI. That an apparently distinct binding mode occurs with only two mutations highlights the ability of ARMs to evolve new recognition strategies and supports the application of neutral theories of evolution to proteinRNA recognition. Copyright (c) 2013 John Wiley & Sons, Ltd

cis-regulatory variation modulates susceptibility to enteric infection in the Drosophila genetic reference panel

Background: Resistance to enteric pathogens is a complex trait at the crossroads of multiple biological processes. We have previously shown in the Drosophila Genetic Reference Panel (DGRP) that resistance to infection is highly heritable, but our understanding of how the effects of genetic variants affect different molecular mechanisms to determine gut immunocompetence is still limited. Results: To address this, we perform a systems genetics analysis of the gut transcriptomes from 38 DGRP lines that were orally infected with Pseudomonas entomophila. We identify a large number of condition-specific, expression quantitative trait loci (local-eQTLs) with infection-specific ones located in regions enriched for FOX transcription factor motifs. By assessing the allelic imbalance in the transcriptomes of 19 F1 hybrid lines from a large round robin design, we independently attribute a robust cis-regulatory effect to only 10% of these detected local-eQTLs. However, additional analyses indicate that many local-eQTLs may act in trans instead. Comparison of the transcriptomes of DGRP lines that were either susceptible or resistant to Pseudomonas entomophila infection reveals nutcracker as the only differentially expressed gene. Interestingly, we find that nutcracker is linked to infection-specific eQTLs that correlate with its expression level and to enteric infection susceptibility. Further regulatory analysis reveals one particular eQTL that significantly decreases the binding affinity for the repressor Broad, driving differential allele-specific nutcracker expression. Conclusions: Our collective findings point to a large number of infection-specific cis- and trans-acting eQTLs in the DGRP, including one common non-coding variant that lowers enteric infection susceptibility

Gene-by-environment modulation of lifespan and weight gain in the murine BXD family.

How lifespan and body weight vary as a function of diet and genetic differences is not well understood. Here we quantify the impact of differences in diet on lifespan in a genetically diverse family of female mice, split into matched isogenic cohorts fed a low-fat chow diet (CD, n = 663) or a high-fat diet (HFD, n = 685). We further generate key metabolic data in a parallel cohort euthanized at four time points. HFD feeding shortens lifespan by 12%: equivalent to a decade in humans. Initial body weight and early weight gains account for longevity differences of roughly 4-6 days per gram. At 500 days, animals on a HFD typically gain four times as much weight as control, but variation in weight gain does not correlate with lifespan. Classic serum metabolites, often regarded as health biomarkers, are not necessarily strong predictors of longevity. Our data indicate that responses to a HFD are substantially modulated by gene-by-environment interactions, highlighting the importance of genetic variation in making accurate individualized dietary recommendations