Environmental stimuli are known to contribute to psoriasis pathogenesis and that of other autoimmune diseases, but the mechanisms are largely unknown. Here we show that the aryl hydrocarbon receptor ...(AhR), a transcription factor that senses environmental stimuli, modulates pathology in psoriasis. AhR-activating ligands reduced inflammation in the lesional skin of psoriasis patients, whereas AhR antagonists increased inflammation. Similarly, AhR signaling via the endogenous ligand FICZ reduced the inflammatory response in the imiquimod-induced model of skin inflammation and AhR-deficient mice exhibited a substantial exacerbation of the disease, compared to AhR-sufficient controls. Nonhematopoietic cells, in particular keratinocytes, were responsible for this hyperinflammatory response, which involved upregulation of AP-1 family members of transcription factors. Thus, our data suggest a critical role for AhR in the regulation of inflammatory responses and open the possibility for novel therapeutic strategies in chronic inflammatory disorders.
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•Physiological AhR signals reduce psoriasis gene expression in patient biopsies•Blocking AhR signals exacerbates psoriasis gene expression in patient biopsies•AhR-deficient mice show exacerbated skin inflammation in imiquimod model•Absence of AhR on mouse or human keratinocytes causes excessive inflammation
The aryl hydrocarbon receptor (AhR), a transcription factor that responds to environmental signals, interacts with a wide range of genes involved in inflammatory responses. Di Meglio et al. show that physiological stimulation of AhR ameliorates skin inflammation in mice and humans.
Transcript regulation is essential for cell function, and misregulation can lead to disease. Despite technologies to survey the transcriptome, we lack a comprehensive understanding of transcript ...kinetics, which limits quantitative biology. This is an acute challenge in embryonic development, where rapid changes in gene expression dictate cell fate decisions. By ultra-high-frequency sampling of Xenopus embryos and absolute normalization of sequence reads, we present smooth gene expression trajectories in absolute transcript numbers. During a developmental period approximating the first 8 weeks of human gestation, transcript kinetics vary by eight orders of magnitude. Ordering genes by expression dynamics, we find that “temporal synexpression” predicts common gene function. Remarkably, a single parameter, the characteristic timescale, can classify transcript kinetics globally and distinguish genes regulating development from those involved in cellular metabolism. Overall, our analysis provides unprecedented insight into the reorganization of maternal and embryonic transcripts and redefines our ability to perform quantitative biology.
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•Ultra-high temporal resolution RNA-seq reveals smooth expression trajectories•Absolute transcript measurements enable calculation of transcriptome kinetics•Transcript accumulation rates vary over eight orders of magnitude during development•Temporal synexpression and timescales distinguish gene functions
Owens et al. present an ultra-high-resolution RNA-seq time course during embryonic development. Using spike-ins to calibrate transcript reads, they measure absolute mRNA transcript numbers and calculate transcriptome kinetics, in some cases, in kilobases per minute per allele. With these data, they find that temporal synexpression and characteristic timescales distinguish gene functions across the transcriptome.
oskar mRNA localization to the posterior of the Drosophila oocyte defines where the abdomen and germ cells form in the embryo. Although this localization requires microtubules and the plus ...end-directed motor, kinesin, its mechanism is controversial and has been proposed to involve active transport to the posterior, diffusion and trapping, or exclusion from the anterior and lateral cortex. By following oskar mRNA particles in living oocytes, we show that the mRNA is actively transported along microtubules in all directions, with a slight bias toward the posterior. This bias is sufficient to localize the mRNA and is reversed in mago, barentsz, and Tropomyosin II mutants, which mislocalize the mRNA anteriorly. Since almost all transport is mediated by kinesin, oskar mRNA localizes by a biased random walk along a weakly polarized cytoskeleton. We also show that each component of the oskar mRNA complex plays a distinct role in particle formation and transport.
The T-box transcription factor Brachyury (T) is essential for formation of the posterior mesoderm and the notochord in vertebrate embryos. Work in the frog and the zebrafish has identified some ...direct genomic targets of Brachyury, but little is known about Brachyury targets in the mouse.
Here we use chromatin immunoprecipitation and mouse promoter microarrays to identify targets of Brachyury in embryoid bodies formed from differentiating mouse ES cells. The targets we identify are enriched for sequence-specific DNA binding proteins and include components of signal transduction pathways that direct cell fate in the primitive streak and tailbud of the early embryo. Expression of some of these targets, such as Axin2, Fgf8 and Wnt3a, is down regulated in Brachyury mutant embryos and we demonstrate that they are also Brachyury targets in the human. Surprisingly, we do not observe enrichment of the canonical T-domain DNA binding sequence 5'-TCACACCT-3' in the vicinity of most Brachyury target genes. Rather, we have identified an (AC)(n) repeat sequence, which is conserved in the rat but not in human, zebrafish or Xenopus. We do not understand the significance of this sequence, but speculate that it enhances transcription factor binding in the regulatory regions of Brachyury target genes in rodents.
Our work identifies the genomic targets of a key regulator of mesoderm formation in the early mouse embryo, thereby providing insights into the Brachyury-driven genetic regulatory network and allowing us to compare the function of Brachyury in different species.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Abstract
Polycystic ovary syndrome (PCOS) is a prevalent endocrine condition characterized by a range of endocrine, reproductive, and metabolic abnormalities. At present, management of women with ...PCOS is suboptimal as treatment is only symptomatic. Clinical and experimental advances in our understanding of PCOS etiology support a pivotal role for androgen neuroendocrine actions in PCOS pathogenesis. Hyperandrogenism is a key PCOS trait and androgen actions play a role in regulating the kisspeptin-/neurokinin B-/dynorphin (KNDy) system. This study aimed to investigate if targeted antagonism of neurokinin B signaling through the neurokinin 3 receptor (NK3R) would reverse PCOS traits in a dihydrotestosterone (DHT)-induced mouse model of PCOS. After 3 months, DHT exposure induced key reproductive PCOS traits of cycle irregularity and ovulatory dysfunction, and PCOS-like metabolic traits including increased body weight; white and brown fat pad weights; fasting serum triglyceride and glucose levels, and blood glucose incremental area under the curve. Treatment with a NK3R antagonist (MLE4901) did not impact the observed reproductive defects. In contrast, following NK3R antagonist treatment, PCOS-like females displayed decreased total body weight, adiposity, and adipocyte hypertrophy, but increased respiratory exchange ratio, suggesting NK3R antagonism altered the metabolic status of the PCOS-like females. NK3R antagonism did not improve circulating serum triglyceride or fasted glucose levels. Collectively, these findings demonstrate that NK3R antagonism may be beneficial in the treatment of adverse metabolic features associated with PCOS and support neuroendocrine targeting in the development of novel therapeutic strategies for PCOS.
The Piwi proteins of the Argonaute superfamily are required for normal germline development in
Drosophila, zebrafish, and mice and associate with 24–30 nucleotide RNAs termed piRNAs. We identify a ...class of 21 nucleotide RNAs, previously named 21U-RNAs, as the piRNAs of
C. elegans. Piwi and piRNA expression is restricted to the male and female germline and independent of many proteins in other small-RNA pathways, including DCR-1. We show that Piwi is specifically required to silence Tc3, but not other Tc/mariner DNA transposons. Tc3 excision rates in the germline are increased at least 100-fold in
piwi mutants as compared to wild-type. We find no evidence for a Ping-Pong model for piRNA amplification in
C. elegans. Instead, we demonstrate that Piwi acts upstream of an endogenous siRNA pathway in Tc3 silencing. These data might suggest a link between piRNA and siRNA function.
Genome of the Western Clawed Frog Xenopus tropicalis Hellsten, Uffe; Harland, Richard M; Gilchrist, Michael J ...
Science (American Association for the Advancement of Science),
04/2010, Letnik:
328, Številka:
5978
Journal Article
Recenzirano
Odprti dostop
The western clawed frog Xenopus tropicalis is an important model for vertebrate development that combines experimental advantages of the African clawed frog Xenopus laevis with more tractable ...genetics. Here we present a draft genome sequence assembly of X. tropicalis. This genome encodes more than 20,000 protein-coding genes, including orthologs of at least 1700 human disease genes. Over 1 million expressed sequence tags validated the annotation. More than one-third of the genome consists of transposable elements, with unusually prevalent DNA transposons. Like that of other tetrapods, the genome of X. tropicalis contains gene deserts enriched for conserved noncoding elements. The genome exhibits substantial shared synteny with human and chicken over major parts of large chromosomes, broken by lineage-specific chromosome fusions and fissions, mainly in the mammalian lineage.
Ovarian tissue is increasingly being collected from cancer patients and cryopreserved for fertility preservation. While the only available option to restore fertility is autologous transplantation, ...this treatment is not appropriate for all patients due to the risk of reintroducing cancer cells and causing disease recurrence. Harnessing the full reproductive potential of this tissue to restore fertility requires the development of culture systems that support oocyte development from the primordial follicle stage. While this has been achieved in the mouse, the goal of obtaining oocytes of sufficient quality to support embryo development has not been reached in higher mammals despite decades of effort. In vivo, primordial follicles gradually exit the resting pool, whereas when primordial follicles are placed into culture, global activation of these follicles occurs. Therefore, the addition of a factor(s) that can regulate primordial follicle activation in vitro may be beneficial to the development of culture systems for ovarian tissue from cancer patients. Several factors have been observed to inhibit follicle activation, including anti-Müllerian hormone, stromal-derived factor 1 and members of the c-Jun-N-terminal kinase pathway. This review summarizes the findings from studies of these factors and discusses their potential integration into ovarian tissue culture strategies for fertility preservation.
Reproductive aging in female mammals is an irreversible process associated with declining oocyte quality, which is the rate-limiting factor to fertility. Here, we show that this loss of oocyte ...quality with age accompanies declining levels of the prominent metabolic cofactor nicotinamide adenine dinucleotide (NAD+). Treatment with the NAD+ metabolic precursor nicotinamide mononucleotide (NMN) rejuvenates oocyte quality in aged animals, leading to restoration in fertility, and this can be recapitulated by transgenic overexpression of the NAD+-dependent deacylase SIRT2, though deletion of this enzyme does not impair oocyte quality. These benefits of NMN extend to the developing embryo, where supplementation reverses the adverse effect of maternal age on developmental milestones. These findings suggest that late-life restoration of NAD+ levels represents an opportunity to rescue female reproductive function in mammals.
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•Declining NAD(P)H is associated with oocyte dysfunction during reproductive aging•Oocyte quality and fertility can be restored by NMN treatment in aged mice•Supplementation of embryo media with NMN improves developmental milestones•SIRT2 overexpression mimics benefits of NMN but is unlikely to mediate its effects
Declining oocyte quality is considered an irreversible feature of aging and is rate limiting for human fertility. Bertoldo et al. show that reversing an age-dependent decline in NAD(P)H restores oocyte quality, embryo development, and functional fertility in aged mice. These findings may be relevant to reproductive medicine.
Linked Editorials
This Editorial is part of a series. To view the other Editorials in this series, visit: http://onlinelibrary.wiley.com/doi/10.1111/bph.12956/; ...http://onlinelibrary.wiley.com/doi/10.1111/bph.12954/; http://onlinelibrary.wiley.com/doi/10.1111/bph.12955/ and http://onlinelibrary.wiley.com/doi/10.1111/bph.13112/
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