ABSTRACT
Low-density lipoprotein cholesterol (LDL-c) is both a therapeutic target and a risk factor for cardiovascular disease (CVD). MicroRNA (miRNA) has been shown to regulate cholesterol homeostasis, and miRNA in blood circulation has been linked to hypercholesterolemia. However, few studies to date have associated miRNA with phenotypes like LDL-c in a healthy population. To this end, we analyzed circulating miRNA in relation to LDL-c in a healthy cohort of 353 participants using two separate bioinformatic approaches. The first approach found that miR-15b-5p and miR-16-5p were upregulated in individuals with at-risk levels of LDL-c. The second approach identified two miRNA clusters, one that positively and a second that negatively correlated with LDL-c. Included in the cluster that positively correlated with LDL-c were miR-15b-5p and miR-16-5p, as well as other miRNA from the miR-15/107, miR-30, and let-7 families. Cross-species analyses suggested that several miRNAs that associated with LDL-c are conserved between mice and humans. Finally, we examined the influence of diet on circulating miRNA. Our results robustly linked circulating miRNA with LDL-c, suggesting that miRNA could be used as biomarkers for hypercholesterolemia or targets for developing cholesterol-lowering drugs.NEW & NOTEWORTHY This study explored the association between circulating microRNA (miRNA) and low-density lipoprotein cholesterol (LDL-c) in a healthy population of 353 participants. Two miRNAs, miR-15b-5p and miR-16-5p, were upregulated in individuals with at-risk LDL-c levels. Several miRNA clusters were positively and negatively correlated with LDL-c and are known to target mRNA involved in lipid metabolism. The study also investigated the influence of diet on circulating miRNA, suggesting potential biomarkers for hypercholesterolemia.
Subject(s)
Cholesterol, LDL , Circulating MicroRNA , MicroRNAs , Humans , Male , Female , Cholesterol, LDL/blood , Middle Aged , Cohort Studies , Adult , Circulating MicroRNA/blood , Circulating MicroRNA/genetics , MicroRNAs/blood , MicroRNAs/genetics , Animals , Mice , Biomarkers/blood , United States , Lipids/blood , Hypercholesterolemia/genetics , Hypercholesterolemia/blood , AgedABSTRACT
BACKGROUND: Obesity is a serious disease with a complex etiology characterized by overaccumulation of adiposity resulting in detrimental health outcomes. Given the liver's critical role in the biological processes that attenuate adiposity accumulation, elucidating the influence of genetics and dietary patterns on hepatic gene expression is fundamental for improving methods of obesity prevention and treatment. To determine how genetics and diet impact obesity development, mice from 22 strains of the genetically diverse recombinant inbred Collaborative Cross (CC) mouse panel were challenged to either a high-protein or high-fat high-sucrose diet, followed by extensive phenotyping and analysis of hepatic gene expression. RESULTS: Over 1000 genes differentially expressed by perturbed dietary macronutrient composition were enriched for biological processes related to metabolic pathways. Additionally, over 9000 genes were differentially expressed by strain and enriched for biological process involved in cell adhesion and signaling. Weighted gene co-expression network analysis identified multiple gene clusters (modules) associated with body fat % whose average expression levels were influenced by both dietary macronutrient composition and genetics. Each module was enriched for distinct types of biological functions. CONCLUSIONS: Genetic background affected hepatic gene expression in the CC overall, but diet macronutrient differences also altered expression of a specific subset of genes. Changes in macronutrient composition altered gene expression related to metabolic processes, while genetic background heavily influenced a broad range of cellular functions and processes irrespective of adiposity. Understanding the individual role of macronutrient composition, genetics, and their interaction is critical to developing therapeutic strategies and policy recommendations for precision nutrition.
ABSTRACT
Defined as chronic excessive accumulation of adiposity, obesity results from long-term imbalance between energy intake and expenditure. The mechanisms behind how caloric imbalance occurs are complex and influenced by numerous biological and environmental factors, especially genetics, and diet. Population-based diet recommendations have had limited success partly due to the wide variation in physiological responses across individuals when they consume the same diet. Thus, it is necessary to broaden our understanding of how individual genetics and diet interact relative to the development of obesity for improving weight loss treatment. To determine how consumption of diets with different macronutrient composition alter adiposity and other obesity-related traits in a genetically diverse population, we analyzed body composition, metabolic rate, clinical blood chemistries, and circulating metabolites in 22 strains of mice from the Collaborative Cross (CC), a highly diverse recombinant inbred mouse population, before and after 8 weeks of feeding either a high protein or high fat high sucrose diet. At both baseline and post-diet, adiposity and other obesity-related traits exhibited a broad range of phenotypic variation based on CC strain; diet-induced changes in adiposity and other traits also depended largely on CC strain. In addition to estimating heritability at baseline, we also quantified the effect size of diet for each trait, which varied by trait and experimental diet. Our findings identified CC strains prone to developing obesity, demonstrate the genotypic and phenotypic diversity of the CC for studying complex traits, and highlight the importance of accounting for genetic differences when making dietary recommendations.
ABSTRACT
Meiotic recombination involves the repair of double-strand break (DSB) precursors as crossovers (COs) or noncrossovers (NCOs). The proper number and distribution of COs is critical for successful chromosome segregation and formation of viable gametes. In budding yeast the majority of COs occurs through a pathway dependent on the ZMM proteins (Zip2-Zip3-Zip4-Spo16, Msh4-Msh5, Mer3), which form foci at CO-committed sites. Here we show that the DNA-damage-response kinase Tel1/ATM limits ZMM-independent recombination. By whole-genome mapping of recombination products, we find that lack of Tel1 results in higher recombination and reduced CO interference. Yet the number of Zip3 foci in tel1Δ cells is similar to wild type, and these foci show normal interference. Analysis of recombination in a tel1Δ zip3Δ double mutant indicates that COs are less dependent on Zip3 in the absence of Tel1. Together these results reveal that in the absence of Tel1, a significant proportion of COs occurs through a non-ZMM-dependent pathway, contributing to a CO landscape with poor interference. We also see a significant change in the distribution of all detectable recombination products in the absence of Tel1, Sgs1, Zip3, or Msh4, providing evidence for altered DSB distribution. These results support the previous finding that DSB interference depends on Tel1, and further suggest an additional level of DSB interference created through local repression of DSBs around CO-designated sites.
Subject(s)
Crossing Over, Genetic , Intracellular Signaling Peptides and Proteins/genetics , Protein Serine-Threonine Kinases/genetics , Saccharomyces cerevisiae Proteins/genetics , Saccharomyces cerevisiae/genetics , DNA Helicases/physiology , DNA-Binding Proteins/physiology , Gene Knockout Techniques , Microtubule-Associated Proteins/physiology , Recombination, Genetic , Saccharomyces cerevisiae Proteins/physiology , Ubiquitin-Protein Ligases/physiologyABSTRACT
Crossovers (COs) play a critical role in ensuring proper alignment and segregation of homologous chromosomes during meiosis. How the cell balances recombination between CO vs. noncrossover (NCO) outcomes is not completely understood. Further lacking is what constrains the extent of DNA repair such that multiple events do not arise from a single double-strand break (DSB). Here, by interpreting signatures that result from recombination genome-wide, we find that synaptonemal complex proteins promote crossing over in distinct ways. Our results suggest that Zip3 (RNF212) promotes biased cutting of the double Holliday-junction (dHJ) intermediate whereas surprisingly Msh4 does not. Moreover, detailed examination of conversion tracts in sgs1 and mms4-md mutants reveal distinct aberrant recombination events involving multiple chromatid invasions. In sgs1 mutants, these multiple invasions are generally multichromatid involving 3-4 chromatids; in mms4-md mutants the multiple invasions preferentially resolve into one or two chromatids. Our analysis suggests that Mus81/Mms4 (Eme1), rather than just being a minor resolvase for COs is crucial for both COs and NCOs in preventing chromosome entanglements by removing 3'- flaps to promote second-end capture. Together our results force a reevaluation of how key recombination enzymes collaborate to specify the outcome of meiotic DNA repair.
Subject(s)
DNA Repair , DNA-Binding Proteins/metabolism , Endonucleases/metabolism , Flap Endonucleases/metabolism , Meiosis , RecQ Helicases/metabolism , Recombination, Genetic , Saccharomyces cerevisiae Proteins/metabolism , Chromatids/metabolism , Chromosome Segregation , DNA Breaks, Double-Stranded , DNA, Cruciform/metabolism , DNA-Binding Proteins/genetics , Endonucleases/genetics , Flap Endonucleases/genetics , Mutation , RecQ Helicases/genetics , Saccharomyces cerevisiae Proteins/genetics , Ubiquitin-Protein Ligases/genetics , Ubiquitin-Protein Ligases/metabolismABSTRACT
Mitochondria must grow with the growing cell to ensure proper cellular physiology and inheritance upon division. We measured the physical size of mitochondrial networks in budding yeast and found that mitochondrial network size increased with increasing cell size and that this scaling relation occurred primarily in the bud. The mitochondria-to-cell size ratio continually decreased in aging mothers over successive generations. However, regardless of the mother's age or mitochondrial content, all buds attained the same average ratio. Thus, yeast populations achieve a stable scaling relation between mitochondrial content and cell size despite asymmetry in inheritance.