The resting state of eukaryotic cells (G0) is relatively uncharacterized. We have applied DNA microarray expression profiling of S. cerevisiae to reveal multiple transitions during a complete 9-day growth cycle between stationary phase (SP) exit and entry. The findings include distinct waves of transcription after the diauxic shift (DS), identification of genes active in SP, and upregulation of over 2500 genes during the first minutes of lag phase. This provides a framework for analyzing large-scale reprogramming of gene expression. Despite global repression, the general transcription machinery is found to be present in quiescent cells but is largely inactive. Genome-wide location analysis by chromatin immunoprecipitation (ChIP on chip) reveals that RNA polymerase II is more predominantly bound at intergenic regions in SP, upstream of hundreds of genes immediately induced upon exit. In contrast to current models of activation-coupled recruitment, the results show that RNA polymerase II is located and maintained upstream of many inactive genes in quiescence.
In many mammalian species, the intestinal epithelium undergoes major changes that allow a dietary transition from mother's milk to the adult diet at the end of the suckling period. These complex developmental changes are the result of a genetic programme intrinsic to the gut tube, but its regulators have not been identified. Here we show that transcriptional repressor B lymphocyte-induced maturation protein 1 (Blimp1) is highly expressed in the developing and postnatal intestinal epithelium until the suckling to weaning transition. Intestine-specific deletion of Blimp1 results in growth retardation and excessive neonatal mortality. Mutant mice lack all of the typical epithelial features of the suckling period and are born with features of an adult-like intestine. We conclude that the suckling to weaning transition is regulated by a single transcriptional repressor that delays epithelial maturation.
Expression profiling is a universal tool, with a range of applications that benefit from the accurate determination of differential gene expression. To allow normalization using endogenous transcript levels, current microarray analyses assume that relatively few transcripts vary, or that any changes that occur are balanced. When normalization using endogenous genes is carried out, changes in expression levels are calculated relative to the behaviour of most of the transcripts. This does not reflect absolute changes if global shifts in messenger RNA populations occur. Using external RNA controls, we have set up microarray experiments to monitor global changes. The levels of most mRNAs were found to change during yeast stationary phase and human heat shock when external controls were included. Even small global changes had a significant effect on the number of genes reported as being differentially expressed. This suggests that global mRNA changes occur more frequently than is assumed at present, and shows that monitoring such effects may be important for the accurate determination of changes in gene expression.
Background:Recent evidence suggests that the gut microbiota plays an important role in human metabolism and energy homeostasis and is therefore a relevant factor in the assessment of metabolic health and flexibility. Understanding of these host–microbiome interactions aids the design of nutritional strategies that act via modulation of the microbiota. Nevertheless, relating gut microbiota composition to host health states remains challenging because of the sheer complexity of these ecosystems and the large degrees of interindividual variation in human microbiota composition.Methods:We assessed fecal microbiota composition and host response patterns of metabolic and inflammatory markers in 10 apparently healthy men subjected to a high-fat high-caloric diet (HFHC, 1300 kcal/day extra) for 4 weeks. DNA was isolated from stool and barcoded 16S rRNA gene amplicons were sequenced. Metabolic health parameters, including anthropomorphic and blood parameters, where determined at t=0 and t=4 weeks.Results:A correlation network approach revealed diet-induced changes in Bacteroides levels related to changes in carbohydrate oxidation rates, whereas the change in Firmicutes correlates with changes in fat oxidation. These results were confirmed by multivariate models. We identified correlations between microbial diversity indices and several inflammation-related host parameters that suggest a relation between diet-induced changes in gut microbiota diversity and inflammatory processes.Conclusions:This approach allowed us to identify significant correlations between abundances of microbial taxa and diet-induced shifts in several metabolic health parameters. Constructed correlation networks provide an overview of these relations, revealing groups of correlations that are of particular interest for explaining host health aspects through changes in the gut microbiota.
BackgroundExcessive exposure to dietary fats is an important factor in the initiation of obesity and metabolic syndrome associated pathologies. The cellular processes associated with the onset and progression of diet-induced metabolic syndrome are insufficiently understood.Principal FindingsTo identify the mechanisms underlying the pathological changes associated with short and long-term exposure to excess dietary fat, hepatic gene expression of ApoE3Leiden mice fed chow and two types of high-fat (HF) diets was monitored using microarrays during a 16-week period. A functional characterization of 1663 HF-responsive genes reveals perturbations in lipid, cholesterol and oxidative metabolism, immune and inflammatory responses and stress-related pathways. The major changes in gene expression take place during the early (day 3) and late (week 12) phases of HF feeding. This is also associated with characteristic opposite regulation of many HF-affected pathways between these two phases. The most prominent switch occurs in the expression of inflammatory/immune pathways (early activation, late repression) and lipogenic/adipogenic pathways (early repression, late activation). Transcriptional network analysis identifies NF-κB, NEMO, Akt, PPARγ and SREBP1 as the key controllers of these processes and suggests that direct regulatory interactions between these factors may govern the transition from early (stressed, inflammatory) to late (pathological, steatotic) hepatic adaptation to HF feeding. This transition observed by hepatic gene expression analysis is confirmed by expression of inflammatory proteins in plasma and the late increase in hepatic triglyceride content. In addition, the genes most predictive of fat accumulation in liver during 16-week high-fat feeding period are uncovered by regression analysis of hepatic gene expression and triglyceride levels.ConclusionsThe transition from an inflammatory to a steatotic transcriptional program, possibly driven by the reciprocal activation of NF-κB and PPARγ regulators, emerges as the principal signature of the hepatic adaptation to excess dietary fat. These findings may be of essential interest for devising new strategies aiming to prevent the progression of high-fat diet induced pathologies.
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