Tissue-specific Variation Research Articles

Hspb1 and Tp53 Mutation and Expression Analysis in Cat Mammary Tumors.

Background Molecular marker based cancer diagnosis gaining more attention in the current genomics era. So, Hspb1 and Tp53 gene characterization and their mRNA expression might be helpful in diagnosis and prognosis of cat mammary adenocarcinoma. It will also add information in comparative cancer genetics and genomics. Objectives Eight tumors of Siamese cats were analyzed to ascertain germ-line and tissue-specific somatic DNA variations of Hspb1 and Tp53 genes along with the ectopic differential expression in tumorous and normal tissues were also analyzed. Materials and Methods Tumorous tissues and peripheral blood from mammary adenocarcinoma affected Siamese cats were collected from the Pet center-UVAS. DNA and RNA were extracted from these tissues to analyze the Hspb1 and Tp53 DNA variants and ectopic expression of their mRNA within cancerous and normal tissues. Results Exon 1 and 3 revealed as hotspots in Hspb1 gene. The 5´UTR region of the exon1 bear six mutation including 3 transitions, 2 transversion and one heterozygous synonymous transversion in two samples at locus c.34C>C/A. Exon 3 has 1 transversion at c.773A>A/T, 3´UTR of this exon harbor two point mutations at 1868A>T and 2193C>T loci. Intron 2 has two alterations at 1490C>C/T and GTCT4del at 1514. Overall up-regulation of Hspb1 gene was observed. While exons 3, 4 and 7 of Tp53 harbor a single variationat c.105A>A/G, c.465T>T/C and c.859G>T respectively. The locus c.1050G>G/A in exon 9 is a heterozygous (G/A) in 3 samples and homozygous (G) in 2 other tumours. Introns 3, 5, 7 and 9 harbor 3, 4, 2 and 7 altered loci respectively. Sixty percent of cancers showed up-regulated trend of Tp53 gene. Conclusions Tumor specific mutations and ectopic expression of Hspb1 and Tp53 genes might be helpful in the diagnosis of the mammary lesions and endorse their involvement in cat mammary neoplasm.

Hsp70 basal levels, a tissue marker of the rate of aging and longevity in mice

Under stressful conditions, the expression of the chaperone Hsp70 is induced, which acts as a cellular defense mechanism. The impairment in this induction has been related to aging, whereas an increased expression has been related to longevity. Nevertheless, it is still not known if the basal levels of Hsp70 can be indicative of the aging rate of different tissues. The aim of this study was to quantify the basal levels of Hsp70 in tissues from female mice throughout their aging process including long-lived mice, as well as from prematurely aging mice (PAM). Adult, old and long-lived (6, 18 and 30months of age, respectively) female ICR-CD1 and Balb/C mice were used. Tissues with mainly mitotic (liver and renal medulla) or post-mitotic (heart, renal cortex, cerebral cortex, spleen) cells and peritoneal leukocytes from these animals as well as from adult PAM and non-prematurely aging mice (NPAM), were studied. Basal levels of Hsp70 were assessed using an ELISA method. The results showed that the aging-associated variation of the levels of Hsp70 followed a different pattern in post-mitotic and mitotic tissues, being lower or higher in old mice comparing to adults, respectively. In all the tissues analyzed the Hsp70 levels from long-lived mice were similar to those from adult animals. In addition, in adult PAM these Hsp70 levels were similar to those in chronologically old animals. In conclusion, Hsp70 basal levels show tissue-specific age-associated variations and are preserved in long-lived animals, demonstrating their role as markers of the rate of aging and longevity.

Quantifying ontogenetic stable isotope variation between dermis and muscle tissue of two pelagic sharks

Comparative analysis of isotope values from different tissues can capture temporal variation in the trophic and foraging behavior of difficult to study large marine predators, reveal- ing either uniform or variable ecological roles over time. The isotopic values (δ 13 C and δ 15 N) of dermis, and muscle tissue of silky Carcharhinus falciformis and blue sharks Prionace glauca sam- pled in the northeast central Pacific were analyzed to quantify ontogenetic inter- and intra-tissue isotopic variation. Consistent differences in δ 15 N values occurred between dermis and muscle tis- sue for both species (2.5 ± 0.4 ‰ and 2.1 ± 0.3 ‰, respectively), while tissue differences in δ 13 C values were more variable between species (2.3 ± 0.6 ‰ and 0.7 ± 0.6 ‰, respectively), likely a result of tissue composition. The overall δ 15 N and δ 13 C values of dermis and muscle were highly correlated for blue sharks and for silky sharks with the exception of silky shark δ 13 C values. This pattern indicates that dermis isotope values are able to provide a proxy for muscle tissue, similar to that previously reported for fin, accepting dermis-specific diettissue discrimination factors. Tissue-specific ontogenetic isotopic variation for the silky shark, and the low regression slope value between dermis and muscle δ 13 C values, however, may suggest that dermis and muscle tissue have different isotopic turnover rates. These data demonstrate that dermis yields valuable isotope data to examine the trophic ecology and feeding/movement behavior of sharks, but further work is required to address dermis-specific turnover rates and diettissue discrimination factors.

Regionalization of surface lipids in insects.

Cuticular hydrocarbons (CHCs) play a critical role in the establishment of the waterproof barrier that prevents dehydration and wetting in insects. While rich data are available on CHC composition in different species, we know little about their distribution and organization. Here, we report on our studies of the surface barrier of the fruit fly Drosophila melanogaster applying a newly developed Eosin Y staining method. The inert Eosin Y penetrates different regions of the adult body at distinct temperatures. By contrast, the larval body takes up the dye rather uniformly and gradually with increasing temperature. Cooling down specimens to 25°C after incubation at higher temperatures restores impermeability. Eosin Y penetration is also sensitive to lipid solvents such as chloroform indicating that permeability depends on CHCs. As in D. melanogaster adult flies, Eosin Y penetration is regionalized in Tenebrio molitor larvae, whereas it is not in Locusta migratoria nymphs. Regionalization of the fly surface implies tissue-specific variation of the genetic or biochemical programmes of CHC production and deposition. The Eosin Y-based map of CHC distribution may serve to identify the respective factors that are activated to accommodate ecological needs.

Cationic Contrast Agent Diffusion Differs Between Cartilage and Meniscus.

Contrast enhanced computed tomography (CECT) is a non-destructive imaging technique used for the assessment of composition and structure of articular cartilage and meniscus. Due to structural and compositional differences between these tissues, diffusion and distribution of contrast agents may differ in cartilage and meniscus. The aim of this study is to determine the diffusion kinematics of a novel iodine based cationic contrast agent (CA2+) in cartilage and meniscus. Cylindrical cartilage and meniscus samples (d = 6 mm, h ≈ 2 mm) were harvested from healthy bovine knee joints (n = 10), immersed in isotonic cationic contrast agent (20 mgI/mL), and imaged using a micro-CT scanner at 26 time points up to 48 h. Subsequently, normalized X-ray attenuation and contrast agent diffusion flux, as well as water, collagen and proteoglycan (PG) contents in the tissues were determined. The contrast agent distributions within cartilage and meniscus were different. In addition, the normalized attenuation and diffusion flux were higher (p < 0.05) in cartilage. Based on these results, diffusion kinematics vary between cartilage and meniscus. These tissue specific variations can affect the interpretation of CECT images and should be considered when cartilage and meniscus are assessed simultaneously.

The C421A (Q141K) polymorphism enhances the 3′-untranslated region (3′-UTR)-dependent regulation of ATP-binding cassette transporter ABCG2

The impact of the gout-causing C421A (Q141K) single nucleotide polymorphism (SNP) on ABC transporter ABCG2 expression and function has been extensively characterized. However, the influence of the C421A SNP on 3′-UTR-dependent ABCG2 regulation has not been analysed so far. To elucidate this matter, we generated vectors for expression of either the ABCG2 coding sequence (ORF) or the ABCG2 ORF fused to its 3′-UTR, inserted the C421A mutation via site-directed mutagenesis and expressed wild-type and C421A-mutated ABCG2 transcripts in HEK293-Tet-On cells. As shown previously, the C421A SNP significantly reduced ABCG2 protein levels in ABCG2 ORF-transfected HEK293-Tet-On cells. Interestingly, the presence of the 3′-UTR in the ABCG2 transcript dramatically reduced ABCG2 protein content in cells transfected with the C421A variant but not significantly in those transfected with ABCG2 wild-type sequence, whereas ABCG2 mRNA levels were similar. siRNA-mediated DICER1 knockdown to reduce cellular microRNA biogenesis and selective mutation of putative microRNA binding sites within the ABCG2 3′-UTR partially antagonized C421A-associated reduction of ABCG2 protein content but did not significantly affect wild-type ABCG2 protein levels. In addition, antagomir-mediated inhibition of two microRNAs (hsa-miR-519c and hsa-miR-328) again partially reversed C421A-associated ABCG2 translational repression, thereby indicating that the C421A SNP may facilitate microRNA-dependent repression of ABCG2 protein translation. We conclude from our results that the C421A SNP may lead to reduced ABCG2 protein levels not only by affecting cellular protein stability but also via enhanced microRNA-dependent ABCG2 repression. Moreover, tissue-specific variation in ABCG2 3′-UTR processing may profoundly affect ABCG2 expression levels in individuals carrying the C421A mutation.

A new view of transcriptome complexity and regulation through the lens of local splicing variations

Alternative splicing (AS) can critically affect gene function and disease, yet mapping splicing variations remains a challenge. Here, we propose a new approach to define and quantify mRNA splicing in units of local splicing variations (LSVs). LSVs capture previously defined types of alternative splicing as well as more complex transcript variations. Building the first genome wide map of LSVs from twelve mouse tissues, we find complex LSVs constitute over 30% of tissue dependent transcript variations and affect specific protein families. We show the prevalence of complex LSVs is conserved in humans and identify hundreds of LSVs that are specific to brain subregions or altered in Alzheimer's patients. Amongst those are novel isoforms in the Camk2 family and a novel poison exon in Ptbp1, a key splice factor in neurogenesis. We anticipate the approach presented here will advance the ability to relate tissue-specific splice variation to genetic variation, phenotype, and disease.

Two HSP90 genes in mandarin fish Siniperca chuatsi: identification, characterization and their specific expression profiles during embryogenesis and under stresses.

HSP90 plays important roles in multiple cellular stress responses. Here, two cytoplasmic HSP90 isoforms, ScHSP90α and ScHSP90β, were identified from Siniperca chuatsi. Their cDNA and gDNA structures, amino acid sequence features, and sequence identities and phylogenetic analysis with other species were described. Their expression profiles during embryonic development in different tissues and under stressful conditions were analyzed using real-time quantitative PCR. During embryogenesis, transcripts of both genes were detected at low levels during the early developmental stages and were up-regulated from appearance of myomere for ScHSP90a and closure of blastopore for ScHSP90β. ScHSP90α showed a tissue-specific variation with high expression in ovary and brain under non-stressed conditions, while ScHSP90β was ubiquitously highly expressed in different tissues. Acute heat shock resulted in a strong up-regulation of ScHSP90α in heart, liver, and head kidney, while it only weakly induced ScHSP90β in these tissues. ScHSP90α was also markedly induced in liver in a time-dependent manner under hypoxia, while the expression of ScHSP90β was not affected by hypoxia. Additionally, Aeromonas hydrophila infection markedly augmented ScHSP90α in head kidney and spleen and mildly up-regulated ScHSP90β in spleen, while suppressing ScHSP90β in head kidney. These results suggest that ScHSP90α and ScHSP90β are differently involved in embryogenesis and under different environmental conditions including high temperature, hypoxia, and bacterial infection. This study will benefit to further clarify the roles of fish HSP90 isoforms in embryogenesis and under stressful conditions and contribute to further study on enhancing stress tolerance and disease resistance of mandarin fish.

Co- and post-transcriptional regulation of Rbm5 and Rbm10 in mouse cells as evidenced by tissue-specific, developmental and disease-associated variation of splice variant and protein expression levels

BackgroundExpression and function of the two RNA binding proteins and regulators of alternative splicing, RBM5 and RBM10, have largely been studied in human tissue and cell lines. The objective of the study described herein was to examine their expression in mouse tissue, in order to lay the framework for comprehensive functional studies using mouse models. MethodsAll RNA variants of Rbm5 and Rbm10 were examined in a range of normal primary mouse tissues. RNA and protein were examined in differentiating C2C12 myoblasts and in denervated and dystonin-deficient mouse skeletal muscle. ResultsAll Rbm5 and Rbm10 variants examined were expressed in all mouse tissues and cell lines. In general, Rbm5 and Rbm10 RNA expression was higher in brain than in skin. RNA expression levels were more varied between cardiac and skeletal muscle, depending on the splice variant: for instance, Rbm10v1 RNA was higher in skeletal than cardiac muscle, whereas Rbm10v3 RNA was higher in cardiac than skeletal muscle. In mouse brain, cardiac and skeletal muscle, RNA encoding an approximately 17kDa potential paralogue of a small human RBM10 isoform was detected, and the protein observed in myoblasts and myotubes. Expression of Rbm5 and Rbm10 RNA remained constant during C2C12 myogenesis, but protein levels significantly decreased. In two muscle disease models, neither Rbm10 nor Rbm5 showed significant transcriptional changes, although significant specific alternative splicing changes of Rbm5 pre-mRNA were observed. Increased RBM10 protein levels were observed following denervation. ConclusionsThe varied co-transcriptional and post-transcriptional regulation aspects of Rbm5 and Rbm10 expression associated with mouse tissues, myogenesis and muscle disease states suggest that a mouse model would be an interesting and useful model in which to study comprehensive functional aspects of RBM5 and RBM10.

A Stigmasterol Containing n-hexane Fraction of Rauvolfia serpentina Methanolic Extract Shows Tissue-Specific Variation of Biocidal and Antioxidant Activities

Tissue-specific variation of stigmasterol in Rauvolfia serpentina and the corresponding biocidal and antioxidant activities of the methanol extract were measured using high-performance thin-layer chromatography. Stigmasterol had the highest concentration in the roots. The highest radical scavenging activity was seen in the root extract (60.94%) at 1 mg.mL−1 DPPH gradient; highest total phenolics content in 1 mg.mL−1 of the root extract was 67 μg of Gallic acid equivalent mg−1 d.w.; highest flavonoids present in the extract was 275 μg of Quercetin equivalent mg−1 d.w. The antibacterial activity was correlated to the amount of stigmasterol, total phenolics, total flavonoids, and antioxidants present in the plant parts.

Exome Sequencing RevealsAGBL5as Novel Candidate Gene and Additional Variants for Retinitis Pigmentosa in Five Turkish Families

Retinitis pigmentosa (RP) is the most common inherited retinal disease with high genetic heterogeneity and variable phenotypes. Characteristic symptoms include night blindness and progressive loss of visual field, leading to blindness. Mutations in >60 genes have been identified to date as causative for RP, and additional candidate genes are assumed. To find the disease-causing mutations in the affected members of five Turkish families, we sequenced whole exomes using an Illumina platform. Among all candidate genes for retinal degeneration we found two previously known sequence variations: a 4 bp deletion in the RPGR gene (c.1662_1665delAGAA; p.Glu555Glyfs*14) and a recently described USH1-causing missense mutation in MYO7A (c.472G>A, p.Gly158Arg). Furthermore, a novel 1 bp deletion in the VCAN gene (c.5118delA; p.Ser1707Valfs*44) was detected as well as a large deletion in EYS, spanning ∼ 400kb and comprising exons 16-26 (p.fs*). In one family, exome analyses of two affected individuals revealed a homozygous missense mutation (c.883G>A; p.Asp295Asn) in the AGBL5 (Agbl5; CCP5) gene, previously not reported to be associated with RP. RNA and protein analyses showed expression in human retina, as well as in mouse retina, brain and testis. Furthermore, cDNA analyses indicate the existence of tissue-specific AGBL5 splice variations in humans. AGBL5/CCP5 immunoreactivity was also visualized in human and mouse retinae. Due to the characteristic RP phenotype in patients carrying the AGBL5 missense mutation we suggest this gene as a candidate for a new form of autosomal recessively inherited RP and recommend further investigation to confirm this hypothesis.

Tissue-specific variation in nonsense mutant transcript level and drug-induced read-through efficiency in the Cln1(R151X) mouse model of INCL.

About 10% of inherited diseases are caused by nonsense mutations [Trends Mol Med 18 (2012) 688], and nonsense suppression drug therapy promoting translation through premature stop codons is an emerging therapeutic approach. Infantile neuronal ceroid lipofuscinosis (INCL), a childhood neurodegenerative disease, results from mutations in the CLN1 gene encoding the lysosomal enzyme, palmitoyl-protein thioesterase 1 (PPT1) [Biochim Biophys Acta 1832 (2013) 1806, Hum Mutat (2012) 63, Biochim Biophys Acta 1832 (2013) 1881]. The nonsense mutation p.R151X is the most common disease-causing CLN1 mutation Hum Mutat (2012) 63. In the novel Cln1(R151X) mouse model of INCL, we found large, tissue-specific variations in Cln1(R151X) mRNA level and PPT1 residual enzyme activity. These tissue-specific differences strongly influenced the read-through efficiency of ataluren (PTC124), a well-known nonsense suppression drug. A two-day treatment with ataluren (10 mg/kg) increased PPT1 enzyme activity in the liver and muscle, but not in any other tissue examined. Our study identifies a new challenge/hurdle for read-through drug therapy: variable efficiency of read-through therapy in the different tissues/organs because of tissue-specific variations in nonsense mutant transcript levels.

Homeostatic Control of the Thyroid-Pituitary Axis: Perspectives for Diagnosis and Treatment.

The long-held concept of a proportional negative feedback control between the thyroid and pituitary glands requires reconsideration in the light of more recent studies. Homeostatic equilibria depend on dynamic inter-relationships between thyroid hormones and pituitary thyrotropin (TSH). They display a high degree of individuality, thyroid-state-related hierarchy, and adaptive conditionality. Molecular mechanisms involve multiple feedback loops on several levels of organization, different time scales, and varying conditions of their optimum operation, including a proposed feedforward motif. This supports the concept of a dampened response and multistep regulation, making the interactions between TSH, FT4, and FT3 situational and mathematically more complex. As a homeostatically integrated parameter, TSH becomes neither normatively fixed nor a precise marker of euthyroidism. This is exemplified by the therapeutic situation with l-thyroxine (l-T4) where TSH levels defined for optimum health may not apply equivalently during treatment. In particular, an FT3–FT4 dissociation, discernible FT3–TSH disjoint, and conversion inefficiency have been recognized in l-T4-treated athyreotic patients. In addition to regulating T4 production, TSH appears to play an essential role in maintaining T3 homeostasis by directly controlling deiodinase activity. While still allowing for tissue-specific variation, this questions the currently assumed independence of the local T3 supply. Rather it integrates peripheral and central elements into an overarching control system. On l-T4 treatment, altered equilibria have been shown to give rise to lower circulating FT3 concentrations in the presence of normal serum TSH. While data on T3 in tissues are largely lacking in humans, rodent models suggest that the disequilibria may reflect widespread T3 deficiencies at the tissue level in various organs. As a consequence, the use of TSH, valuable though it is in many situations, should be scaled back to a supporting role that is more representative of its conditional interplay with peripheral thyroid hormones. This reopens the debate on the measurement of free thyroid hormones and encourages the identification of suitable biomarkers. Homeostatic principles conjoin all thyroid parameters into an adaptive context, demanding a more flexible interpretation in the accurate diagnosis and treatment of thyroid dysfunction.

Metabolome analysis of 20 taxonomically related benzylisoquinoline alkaloid-producing plants.

BackgroundRecent progress toward the elucidation of benzylisoquinoline alkaloid (BIA) metabolism has focused on a small number of model plant species. Current understanding of BIA metabolism in plants such as opium poppy, which accumulates important pharmacological agents such as codeine and morphine, has relied on a combination of genomics and metabolomics to facilitate gene discovery. Metabolomics studies provide important insight into the primary biochemical networks underpinning specialized metabolism, and serve as a key resource for metabolic engineering, gene discovery, and elucidation of governing regulatory mechanisms. Beyond model plants, few broad-scope metabolomics reports are available for the vast number of plant species known to produce an estimated 2500 structurally diverse BIAs, many of which exhibit promising medicinal properties.ResultsWe applied a multi-platform approach incorporating four different analytical methods to examine 20 non-model, BIA-accumulating plant species. Plants representing four families in the Ranunculales were chosen based on reported BIA content, taxonomic distribution and importance in modern/traditional medicine. One-dimensional 1H NMR-based profiling quantified 91 metabolites and revealed significant species- and tissue-specific variation in sugar, amino acid and organic acid content. Mono- and disaccharide sugars were generally lower in roots and rhizomes compared with stems, and a variety of metabolites distinguished callus tissue from intact plant organs. Direct flow infusion tandem mass spectrometry provided a broad survey of 110 lipid derivatives including phosphatidylcholines and acylcarnitines, and high-performance liquid chromatography coupled with UV detection quantified 15 phenolic compounds including flavonoids, benzoic acid derivatives and hydroxycinnamic acids. Ultra-performance liquid chromatography coupled with high-resolution Fourier transform mass spectrometry generated extensive mass lists for all species, which were mined for metabolites putatively corresponding to BIAs. Different alkaloids profiles, including both ubiquitous and potentially rare compounds, were observed.ConclusionsExtensive metabolite profiling combining multiple analytical platforms enabled a more complete picture of overall metabolism occurring in selected plant species. This study represents the first time a metabolomics approach has been applied to most of these species, despite their importance in modern and traditional medicine. Coupled with genomics data, these metabolomics resources serve as a key resource for the investigation of BIA biosynthesis in non-model plant species.Electronic supplementary materialThe online version of this article (doi:10.1186/s12870-015-0594-2) contains supplementary material, which is available to authorized users.

Triterpenoid profiling and functional characterization of the initial genes involved in isoprenoid biosynthesis in neem (Azadirachta indica).

BackgroundNeem tree (Azadirachta indica) is one of the richest sources of skeletally diverse triterpenoids and they are well-known for their broad-spectrum pharmacological and insecticidal properties. However, the abundance of Neem triterpenoids varies among the tissues. Here, we delineate quantitative profiling of fifteen major triterpenoids across various tissues including developmental stages of kernel and pericarp, flower, leaf, stem and bark using UPLC-ESI(+)-HRMS based profiling. Transcriptome analysis was used to identify the initial genes involved in isoprenoid biosynthesis. Based on transcriptome analysis, two short-chain prenyltransferases and squalene synthase (AiSQS) were cloned and functionally characterized.ResultsQuantitative profiling revealed differential abundance of both total and individual triterpenoid content across various tissues. RNA from tissues with high triterpenoid content (fruit, flower and leaf) were pooled to generate 79.08 million paired-end reads using Illumina GA ΙΙ platform. 41,140 transcripts were generated by d e novo assembly. Transcriptome annotation led to the identification of the putative genes involved in isoprenoid biosynthesis. Two short-chain prenyltransferases, geranyl diphosphate synthase (AiGDS) and farnesyl diphosphate synthase (AiFDS) and squalene synthase (AiSQS) were cloned and functionally characterized using transcriptome data. RT-PCR studies indicated five-fold and ten-fold higher relative expression level of AiSQS in fruits as compared to leaves and flowers, respectively.ConclusionsTriterpenoid profiling indicated that there is tissue specific variation in their abundance. The mature seed kernel and initial stages of pericarp were found to contain the highest amount of limonoids. Furthermore, a wide diversity of triterpenoids, especially C-seco triterpenoids were observed in kernel as compared to the other tissues. Pericarp, flower and leaf contained mainly ring-intact triterpenoids. The initial genes such as AiGDS, AiFDS and AiSQS involved in the isoprenoids biosynthesis have been functionally characterized. The expression levels of AiFDS and AiSQS were found to be in correlation with the total triterpenoid content in individual tissues.Electronic supplementary materialThe online version of this article (doi:10.1186/s12870-015-0593-3) contains supplementary material, which is available to authorized users.

Tissue-specific sequence and structural environments of lysine acetylation sites.

Lysine acetylation is a widespread reversible post-translational modification that regulates a broad spectrum of biological activities across various cellular compartments, cell types, tissues, and disease states. While compartment-specific trends in lysine acetylation have recently been investigated, its tissue-specific preferences remain unexplored. Here we present a comprehensive tissue-based analysis of sequence and structural features of lysine acetylation sites (LASs) based on the recent experimental data of Lundby et al. (2012). We show that acetylated substrates are characterized by tissue-specific motifs both in linear amino acid sequence and in spatial environments. We further demonstrate that the general tendency of LASs to reside in ordered regions and, specifically, in α-helices, is also subject to tissue specific variation. In line with previous findings we show that LASs are generally more evolutionarily conserved than non-LASs, especially in proteins with known function and in structurally regular regions. On the other hand, as revealed by metabolic pathway analysis, LASs have diverse cellular functions in different tissues and are frequently associated with tissue-specific protein domains. These findings may imply the existence of tissue-specific lysine acetyltransferases (KATs) and lysine deacetylases (KDACs).

Somatic expression of unc-54 and vha-6 mRNAs declines but not pan-neuronal rgef-1 and unc-119 expression in aging Caenorhabditis elegans.

Aging is a highly controlled biological process characterized by a progressive deterioration of various cellular activities. One of several hallmarks of aging describes a link to transcriptional alteration, suggesting that it may impact the steady-state mRNA levels. We analyzed the mRNA steady-state levels of polyCAG-encoding transgenes and endogenous genes under the control of well-characterized promoters for intestinal (vha-6), muscular (unc-54, unc-15) and pan-neuronal (rgef-1, unc-119) expression in the nematode Caenorhabditis elegans. We find that there is not a uniform change in transcriptional profile in aging, but rather a tissue-specific difference in the mRNA levels of these genes. While levels of mRNA in the intestine (vha-6) and muscular (unc-54, unc-15) cells decline with age, pan-neuronal tissue shows more stable mRNA expression (rgef-1, unc-119) which even slightly increases with the age of the animals. Our data on the variations in the mRNA abundance from exemplary cases of endogenous and transgenic gene expression contribute to the emerging evidence for tissue-specific variations in the aging process.

Macrophage phenotype modulation to control synovial inflammation

Macrophage phenotype modulation to control synovial inflammation

Cell-type-specific enrichment of risk-associated regulatory elements at ovarian cancer susceptibility loci.

Understanding the regulatory landscape of the human genome is a central question in complex trait genetics. Most single-nucleotide polymorphisms (SNPs) associated with cancer risk lie in non-protein-coding regions, implicating regulatory DNA elements as functional targets of susceptibility variants. Here, we describe genome-wide annotation of regions of open chromatin and histone modification in fallopian tube and ovarian surface epithelial cells (FTSECs, OSECs), the debated cellular origins of high-grade serous ovarian cancers (HGSOCs) and in endometriosis epithelial cells (EECs), the likely precursor of clear cell ovarian carcinomas (CCOCs). The regulatory architecture of these cell types was compared with normal human mammary epithelial cells and LNCaP prostate cancer cells. We observed similar positional patterns of global enhancer signatures across the three different ovarian cancer precursor cell types, and evidence of tissue-specific regulatory signatures compared to non-gynecological cell types. We found significant enrichment for risk-associated SNPs intersecting regulatory biofeatures at 17 known HGSOC susceptibility loci in FTSECs (P = 3.8 × 10(-30)), OSECs (P = 2.4 × 10(-23)) and HMECs (P = 6.7 × 10(-15)) but not for EECs (P = 0.45) or LNCaP cells (P = 0.88). Hierarchical clustering of risk SNPs conditioned on the six different cell types indicates FTSECs and OSECs are highly related (96% of samples using multi-scale bootstrapping) suggesting both cell types may be precursors of HGSOC. These data represent the first description of regulatory catalogues of normal precursor cells for different ovarian cancer subtypes, and provide unique insights into the tissue specific regulatory variation with respect to the likely functional targets of germline genetic susceptibility variants for ovarian cancer.

Comparative analysis of sequence feature and expression of two heat shock cognate 70 genes in mandarin fish Siniperca chuatsi

Heat shock cognate protein 70 (HSC70) is a molecular chaperone that plays essential roles in maintaining the cellular protein homeostasis. In this study, two HSC70 isoforms were identified and characterized from mandarin fish Siniperca chuatsi. They have similar sequence structures, containing seven introns in their coding regions and sharing 94% similarity of their deduced amino acid sequences with 38 substitutions. Transcripts of both isoforms were detected throughout the embryogenesis, at low levels during the early developmental stages and up-regulated at blastula for ScHSC70-1 and appearance of myomere stage for ScHSC70-2. They were ubiquitously expressed in tissues under normal conditions, whereas with tissue-specific variation. Following acute heat shock at 34°C, the expression of ScHSC70-1 showed no significant changes in the liver, and just a modest increase in the heart and head kidney, while the ScHSC70-2 mRNA levels were markedly up-regulated in these tissues. Compared with their expression under gradual heat shock, the ScHSC70-2 mRNA was rising at a higher rate under fast heat shock, whereas the ScHSC70-1 mRNA increasing rate was lower under fast heat shock. Under hypoxia, transcripts of ScHSC70-1 were not significantly changed, while the expression of ScHSC70-2 was suppressed. Aeromonas hydrophila infection significantly increased the ScHSC70-1 mRNA levels in the head kidney and spleen on early infective stages, while failed to have any significant impact on the expression of ScHSC70-2 in both immune tissues. These results suggest that ScHSC70-1 and ScHSC70-2 are differently involved in the embryogenesis and the stress responses of high temperature, hypoxia and bacterial infection. This study will contribute to further study on enhancing stress tolerance and disease resistance of mandarin fish.