Aneuploidy and proteotoxic stress in cancer

Although nearly ubiquitous in cancer, aneuploidy exerts detrimental effects on human cells. We recently demonstrated that aneuploid human cells exhibit impaired heat shock factor protein 1 (HSF1) and HSP90 function, suggesting a functional link between two recurring features of cancer cells: aneuploidy and proteotoxic stress. Further, our fi ndings implicate HSF1 as a key factor in mitigating the effects of aneuploid

The Origin of a New Sex Chromosome by Introgression between Two Stickleback Fishes.

Introgression is increasingly recognized as a source of genetic diversity that fuels adaptation. Its role in the evolution of sex chromosomes, however, is not well known. Here, we confirm the hypothesis that the Y chromosome in the ninespine stickleback, Pungitius pungitius, was established by introgression from the Amur stickleback, P. sinensis. Using whole genome resequencing, we identified a large region of Chr 12 in P. pungitius that is diverged between males and females. Within but not outside of this region, several lines of evidence show that the Y chromosome of P. pungitius shares a most recent common ancestor not with the X chromosome, but with the homologous chromosome in P. sinensis. Accumulation of repetitive elements and gene expression changes on the new Y are consistent with a young sex chromosome in early stages of degeneration, but other hallmarks of Y chromosomes have not yet appeared. Our findings indicate that porous species boundaries can trigger rapid sex chromosome evolution

Myriocin-induced adaptive laboratory evolution of an industrial strain of Saccharomyces cerevisiae reveals its potential to remodel lipid composition and heat tolerance

The modification of lipid composition allows cells to adjust membrane biophysical properties in response to changes in environmental temperature. Here, we use adaptive laboratory evolution (ALE) in the presence of myriocin, a sphingolipid (SLs) biosynthesis inhibitor, to remodel the lipid profile of an industrial yeast strain (LH) of Saccharomyces cerevisiae. The approach enabled to obtain a heterogeneous population (LHev) of myriocin-tolerant evolved clones characterized by its growth capacity at high temperature. Myriocin exposure also caused tolerance to soraphen A, an inhibitor of the acetyl-CoA carboxylase Acc1, the rate-limiting enzyme in fatty acid de novo production, supporting a change in lipid metabolism during ALE. In line with this, characterization of two randomly selected clones, LH03 and LH09, showed the presence of lipids with increased saturation degree and reduced acyl length. In addition, the clone LH03, which displays the greater improvement in fitness at 40°C, exhibited higher SL content as compared with the parental strain. Analysis of the LH03 and LH09 genomes revealed a loss of chromosomes affecting genes that have a role in fatty acid synthesis and elongation. The link between ploidy level and growth at high temperature was further supported by the analysis of a fully isogenic set of yeast strains with ploidy between 1N and 4N which showed that the loss of genome content provides heat tolerance. Consistent with this, a thermotolerant evolved population (LH40°) generated from the parental LH strain by heat-driven ALE exhibited a reduction in the chromosome copy number. Thus, our results identify myriocin-driven evolution as a powerful approach to investigate the mechanisms of acquired thermotolerance and to generate improved strains

HP1-β is required for development of the cerebral neocortex and neuromuscular junctions

HP1 proteins are thought to be modulators of chromatin organization in all mammals, yet their exact physiological function remains unknown. In a first attempt to elucidate the function of these proteins in vivo, we disrupted the murine Cbx1 gene, which encodes the HP1-β isotype, and show that the Cbx1−/−-null mutation leads to perinatal lethality. The newborn mice succumbed to acute respiratory failure, whose likely cause is the defective development of neuromuscular junctions within the endplate of the diaphragm. We also observe aberrant cerebral cortex development in Cbx1−/− mutant brains, which have reduced proliferation of neuronal precursors, widespread cell death, and edema. In vitro cultures of neurospheres from Cbx1−/− mutant brains reveal a dramatic genomic instability. Our results demonstrate that HP1 proteins are not functionally redundant and that they are likely to regulate lineage-specific changes in heterochromatin organization

Global dosage compensation is ubiquitous in Lepidoptera, but counteracted by the masculinization of the Z chromosome

While chromosome-wide dosage compensation of the X chromosome has been found in many species, studies in ZW clades have indicated that compensation of the Z is more localized and/or incomplete. In the ZW Lepidoptera, some species show complete compensation of the Z chromosome, while others lack full equalization, but what drives these inconsistencies is unclear. Here, we compare patterns of male and female gene expression on the Z chromosome of two closely related butterfly species, Papilio xuthus and Papilio machaon, and in multiple tissues of two moths species, Plodia interpunctella and Bombyx mori, which were previously found to differ in the extent to which they equalize Z-linked gene expression between the sexes. We find that, while some species and tissues seem to have incomplete dosage compensation, this is in fact due to the accumulation of male-biased genes and the depletion of female-biased genes on the Z chromosome. Once this is accounted for, the Z chromosome is fully compensated in all four species, through the up-regulation of Z expression in females and in some cases additional down-regulation in males. We further find that both sex-biased genes and Z-linked genes have increased rates of expression divergence in this clade, and that this can lead to fast shifts in patterns of gene expression even between closely related species. Taken together, these results show that the uneven distribution of sex-biased genes on sex chromosomes can confound conclusions about dosage compensation and that Z chromosome-wide dosage compensation is not only possible but ubiquitous among Lepidoptera

Mol. Syst. Biol.

Extra chromosome copies markedly alter the physiology of eukaryotic cells, but the underlying reasons are not well understood. We created human trisomic and tetrasomic cell lines and determined the quantitative changes in their transcriptome and proteome in comparison with their diploid counterparts. We found that whereas transcription levels reflect the chromosome copy number changes, the abundance of some proteins, such as subunits of protein complexes and protein kinases, is reduced toward diploid levels. Furthermore, using the quantitative data we investigated the changes of cellular pathways in response to aneuploidy. This analysis revealed specific and uniform alterations in pathway regulation in cells with extra chromosomes. For example, the DNA and RNA metabolism pathways were downregulated, whereas several pathways such as energy metabolism, membrane metabolism and lysosomal pathways were upregulated. In particular, we found that the p62-dependent selective autophagy is activated in the human trisomic and tetrasomic cells. Our data present the first broad proteomic analysis of human cells with abnormal karyotypes and suggest a uniform cellular response to the presence of an extra chromosome

Unique features of the transcriptional response to model aneuploidy in human cells

Background: Aneuploidy, a karyotype deviating from multiples of a haploid chromosome set, affects the physiology of eukaryotes. In humans, aneuploidy is linked to pathological defects such as developmental abnormalities, mental retardation or cancer, but the underlying mechanisms remain elusive. There are many different types and origins of aneuploidy, but whether there is a uniform cellular response to aneuploidy in human cells has not been addressed so far. Results: Here we evaluate the transcription profiles of eleven trisomic and tetrasomic cell lines and two cell lines with complex aneuploid karyotypes. We identify a characteristic aneuploidy response pattern defined by upregulation of genes linked to endoplasmic reticulum, Golgi apparatus and lysosomes, and downregulation of DNA replication, transcription as well as ribosomes. Strikingly, complex aneuploidy elicits the same transcriptional changes as trisomy. To uncover the triggers of the response, we compared the profiles with transcription changes in human cells subjected to stress conditions. Interestingly, we found an overlap only with the response to treatment with the autophagy inhibitor bafilomycin A1. Finally, we identified 23 genes whose expression is significantly altered in all aneuploids and which may thus serve as aneuploidy markers. Conclusions: Our analysis shows that despite the variability in chromosome content, aneuploidy triggers uniform transcriptional response in human cells. A common response independent of the type of aneuploidy might be exploited as a novel target for cancer therapy. Moreover, the potential aneuploidy markers identified in our analysis might represent novel biomarkers to assess the malignant potential of a tumor

Complete mitochondrial genomes from the ferns \u3ci\u3eOphioglossum californicum\u3c/i\u3e and \u3ci\u3ePsilotum nudum\u3c/i\u3e are highly repetitive with the largest organellar introns

Currently, complete mitochondrial genomes (mitogenomes) are available from all major land plant lineages except ferns. Sequencing of fern mitogenomes could shed light on the major evolutionary transitions that established mitogenomic diversity among extant lineages. In this study, we generated complete mitogenomes from the adder’s tongue fern (Ophioglossum californicum) and the whisk fern (Psilotum nudum). The Psilotum mitogenome (628 kb) contains a rich complement of genes and introns, some of which are the largest of any green plant organellar genome. In the Ophioglossum mitogenome (372 kb), gene and intron content is slightly reduced, including the loss of all four mitochondrial ccm genes. Transcripts of nuclear Ccm genes also were not detected, suggesting loss of the entire mitochondrial cytochrome c maturation pathway from Ophioglossum. Both fern mitogenomes are highly repetitive, yet they show extremely low levels of active recombination. Transcriptomic sequencing uncovered ~1000 sites of C-to-U RNA editing in both species, plus a small number (\u3c 60) of U-to-C edit sites. Overall, the first mitochondrial genomes of ferns show a mix of features shared with lycophytes and/or seed plants and several novel genomic features, enabling a robust reconstruction of the mitogenome in the common ancestor of vascular plants

Osmolytes: Proline metabolism in plants as sensors of abiotic stress

Proline accumulation occurs in a large range of plant species in retaliation to the numerous abiotic stresses. An exclusive research pattern suggests there is a pragmatic relation between proline accumulation and plant stress tolerance. In this review, we will discuss the metabolism of proline accumulation and its role in stress tolerance in plants. Pertaining to the literature cited clearly indicates that not only does it acts as an osmolyte, it also plays important roles during stress as a metal chelator and an antioxidative defence molecule. Moreover, when applied exogenously at low concentrations, proline enhanced stress tolerance in plants. However, some reports point out adverse effects of proline when applied at higher doses. Role of proline gene in seed germination, flowering and other developmental programmes; thus creation of transgene overexpressing this gene would provide better and robust plants. In this context this review gives a detailed account of different proline gene over-expressed in all the trans-genic crops so far