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Genomics
Vitamin A-Retinoic Acid Signaling Regulates Hematopoietic Stem Cell Dormancy
May 08, 2017   Cell
Cabezas-Wallscheid N, Buettner F, Sommerkamp P, Klimmeck D, Ladel L,   . . . . . .   , Benes V, Dick TP, Rieger MA, Stegle O, Trumpp A
Vitamin A-Retinoic Acid Signaling Regulates Hematopoietic Stem Cell Dormancy
May 08, 2017
Cell
Dormant hematopoietic stem cells (dHSCs) are atop the hematopoietic hierarchy. The molecular identity of dHSCs and the mechanisms regulating their maintenance or exit from dormancy remain uncertain. Here, we use single-cell RNA sequencing (RNA-seq) analysis to show that the transition from dormancy toward cell-cycle entry is a continuous developmental path associated with upregulation of biosynthetic processes rather than a stepwise progression. In addition, low Myc levels and high expression of a retinoic acid program are characteristic for dHSCs. To follow the behavior of dHSCs in situ, a Gprc5c-controlled reporter mouse was established. Treatment with all-trans retinoic acid antagonizes stress-induced activation of dHSCs by restricting protein translation and levels of reactive oxygen species (ROS) and Myc. Mice maintained on a vitamin A-free diet lose HSCs and show a disrupted re-entry into dormancy after exposure to inflammatory stress stimuli. Our results highlight the impact of dietary vitamin A on the regulation of cell-cycle-mediated stem cell plasticity. VIDEO ABSTRACT. Copyright © 2017. Published by Elsevier Inc.
Discovery of nitrate-CPK-NLP signalling in central nutrient-growth networks
May 10, 2017   Nature Add nature.com free-link Cancel
Liu KH, Niu Y, Konishi M, Wu Y, Du H,   . . . . . .   , Ishida T, Zhang C, Shokat K, Yanagisawa S, Sheen J
Discovery of nitrate-CPK-NLP signalling in central nutrient-growth networks
May 10, 2017
Nature
Nutrient signalling integrates and coordinates gene expression, metabolism and growth. However, its primary molecular mechanisms remain incompletely understood in plants and animals. Here we report unique Ca2+ signalling triggered by nitrate with live imaging of an ultrasensitive biosensor in Arabidopsis leaves and roots. A nitrate-sensitized and targeted functional genomic screen identifies subgroup III Ca2+-sensor protein kinases (CPKs) as master regulators that orchestrate primary nitrate responses. A chemical switch with the engineered mutant CPK10(M141G) circumvents embryo lethality and enables conditional analyses of cpk10 cpk30 cpk32 triple mutants to define comprehensive nitrate-associated regulatory and developmental programs. Nitrate-coupled CPK signalling phosphorylates conserved NIN-LIKE PROTEIN (NLP) transcription factors to specify the reprogramming of gene sets for downstream transcription factors, transporters, nitrogen assimilation, carbon/nitrogen metabolism, redox, signalling, hormones and proliferation. Conditional cpk10 cpk30 cpk32 and nlp7 mutants similarly impair nitrate-stimulated system-wide shoot growth and root establishment. The nutrient-coupled Ca2+ signalling network integrates transcriptome and cellular metabolism with shoot-root coordination and developmental plasticity in shaping organ biomass and architecture.
Comparative transcriptome analysis of Rimicaris sp. reveals novel molecular features associated with survival in deep-sea hydrothermal vent
May 18, 2017   Scientific Reports
Zhang J, Sun QL, Luan ZD, Lian C, Sun L
Comparative transcriptome analysis of Rimicaris sp. reveals novel molecular features associated with survival in deep-sea hydrothermal vent
May 18, 2017
Scientific Reports
Shrimp of the family Alvinocarididae are the predominant megafauna of deep-sea hydrothermal vents. However, genome information on this family is currently unavailable. In the present study, by employing Illumina sequencing, we performed the first de novo transcriptome analysis of the gills of the shrimp Rimicaris sp. from the hydrothermal vent in Desmos, Manus Basin. The analysis was conducted in a comparative manner with the shrimp taken directly from the vent (GR samples) and the shrimp that had been maintained for ten days under normal laboratory condition (mGR samples). Among the 128,938 unigenes identified, a large number of differentially expressed genes (DEGs) between the GR and mGR samples were detected, including 2365 and 1607 genes significantly upregulated and downregulated, respectively, in GR. The DEGs covered diverse functional categories. Most of the DEGs associated with immunity were downregulated in GR, while most of the DEGs associated with sulfur metabolism and detoxification were upregulated in GR. These results provide the first comprehensive transcriptomic resource for hydrothermal vent Rimicaris and revealed varied categories of genes likely involved in deep-sea survival.
Chromatin states define tumour-specific T cell dysfunction and reprogramming
May 17, 2017   Nature Add nature.com free-link Cancel
Philip M, Fairchild L, Sun L, Horste EL, Camara S, Shakiba M, Scott AC, Viale A, Lauer P, Merghoub T, Hellmann MD, Wolchok JD, Leslie CS, Schietinger A
Chromatin states define tumour-specific T cell dysfunction and reprogramming
May 17, 2017
Nature
Tumour-specific CD8 T cells in solid tumours are dysfunctional, allowing tumours to progress. The epigenetic regulation of T cell dysfunction and therapeutic reprogrammability (for example, to immune checkpoint blockade) is not well understood. Here we show that T cells in mouse tumours differentiate through two discrete chromatin states: a plastic dysfunctional state from which T cells can be rescued, and a fixed dysfunctional state in which the cells are resistant to reprogramming. We identified surface markers associated with each chromatin state that distinguished reprogrammable from non-reprogrammable PD1hi dysfunctional T cells within heterogeneous T cell populations from tumours in mice; these surface markers were also expressed on human PD1hi tumour-infiltrating CD8 T cells. Our study has important implications for cancer immunotherapy as we define key transcription factors and epigenetic programs underlying T cell dysfunction and surface markers that predict therapeutic reprogrammability.
Conversion of adult endothelium to immunocompetent haematopoietic stem cells
May 17, 2017   Nature Add nature.com free-link Cancel
Lis R, Karrasch CC, Poulos MG, Kunar B, Redmond D,   . . . . . .   , Elemento O, Speck NA, Butler JM, Scandura JM, Rafii S
Conversion of adult endothelium to immunocompetent haematopoietic stem cells
May 17, 2017
Nature
Developmental pathways that orchestrate the fleeting transition of endothelial cells into haematopoietic stem cells remain undefined. Here we demonstrate a tractable approach for fully reprogramming adult mouse endothelial cells to haematopoietic stem cells (rEC-HSCs) through transient expression of the transcription-factor-encoding genes Fosb, Gfi1, Runx1, and Spi1 (collectively denoted hereafter as FGRS) and vascular-niche-derived angiocrine factors. The induction phase (days 0-8) of conversion is initiated by expression of FGRS in mature endothelial cells, which results in endogenous Runx1 expression. During the specification phase (days 8-20), RUNX1+ FGRS-transduced endothelial cells commit to a haematopoietic fate, yielding rEC-HSCs that no longer require FGRS expression. The vascular niche drives a robust self-renewal and expansion phase of rEC-HSCs (days 20-28). rEC-HSCs have a transcriptome and long-term self-renewal capacity similar to those of adult haematopoietic stem cells, and can be used for clonal engraftment and serial primary and secondary multi-lineage reconstitution, including antigen-dependent adaptive immune function. Inhibition of TGFβ and CXCR7 or activation of BMP and CXCR4 signalling enhanced generation of rEC-HSCs. Pluripotency-independent conversion of endothelial cells into autologous authentic engraftable haematopoietic stem cells could aid treatment of haematological disorders.
Lipidomic profiling reveals distinct differences in plasma lipid composition in healthy, prediabetic and type 2 diabetic individuals
May 15, 2017   GigaScience
Zhong H, Fang C, Fan Y, Lu Y, Wen B,   . . . . . .   , Madsen L, Kristiansen K, Ni C, Li J, Liu S
Lipidomic profiling reveals distinct differences in plasma lipid composition in healthy, prediabetic and type 2 diabetic individuals
May 15, 2017
GigaScience
The relationship between dyslipidemia and type 2 diabetes mellitus (T2D) has been extensively reported, but the global lipid profiles, especially in the East Asia population, associated with the development of T2D remain to be characterized. Liquid chromatography coupled to tandem mass spectrometry was applied to detect the global lipidome in the fasting plasma of 293 Chinese individuals, including 114 T2D patients, 81 prediabetic subjects and 98 individuals with normal glucose tolerance (NGT). Both qualitative and quantitative analyses revealed a gradual change in plasma lipid features going from NGT individuals over prediabetic to T2D individuals with T2D patients exhibiting characteristics close to those in prediabetic individuals, whereas they differed significantly from individuals with NGT. We constructed and validated a random forest classifier with 28 lipidomic features that effectively discriminated T2D from NGT or prediabetes. Most of the selected features significantly correlated with diabetic clinical indices. Hydroxybutyrylcarnitine was positively correlated with fasting plasma glucose, 2-hour postprandial glucose, glycated hemoglobin, and insulin resistance index (HOMA-IR). Lysophosphatidylcholines such as lysophosphatidylcholine (18:0), lysophosphatidylcholine (18:1) and lysophosphatidylcholine (18:2) were all negatively correlated with HOMA-IR. The altered plasma lipidome in Chinese T2D and prediabetic subjects suggests that lipid features may play a role in the pathogenesis of T2D and that such features may provide a basis for evaluating risk and monitoring disease development.
The evolutionary significance of polyploidy
May 15, 2017   Nature Reviews. Genetics
Van de Peer Y, Mizrachi E, Marchal K
The evolutionary significance of polyploidy
May 15, 2017
Nature Reviews. Genetics
Polyploidy, or the duplication of entire genomes, has been observed in prokaryotic and eukaryotic organisms, and in somatic and germ cells. The consequences of polyploidization are complex and variable, and they differ greatly between systems (clonal or non-clonal) and species, but the process has often been considered to be an evolutionary 'dead end'. Here, we review the accumulating evidence that correlates polyploidization with environmental change or stress, and that has led to an increased recognition of its short-term adaptive potential. In addition, we discuss how, once polyploidy has been established, the unique retention profile of duplicated genes following whole-genome duplication might explain key longer-term evolutionary transitions and a general increase in biological complexity.
Comparative transcriptomics in human and mouse
May 08, 2017   Nature Reviews. Genetics
Breschi A, Gingeras TR, Guigó R
Comparative transcriptomics in human and mouse
May 08, 2017
Nature Reviews. Genetics
Cross-species comparisons of genomes, transcriptomes and gene regulation are now feasible at unprecedented resolution and throughput, enabling the comparison of human and mouse biology at the molecular level. Insights have been gained into the degree of conservation between human and mouse at the level of not only gene expression but also epigenetics and inter-individual variation. However, a number of limitations exist, including incomplete transcriptome characterization and difficulties in identifying orthologous phenotypes and cell types, which are beginning to be addressed by emerging technologies. Ultimately, these comparisons will help to identify the conditions under which the mouse is a suitable model of human physiology and disease, and optimize the use of animal models.
Transcriptome and metabolite analysis identifies nitrogen utilization genes in tea plant (Camellia sinensis)
May 11, 2017   Scientific Reports
Li W, Xiang F, Zhong M, Zhou L, Liu H, Li S, Wang X
Transcriptome and metabolite analysis identifies nitrogen utilization genes in tea plant (Camellia sinensis)
May 11, 2017
Scientific Reports
Applied nitrogen (N) fertilizer significantly increases the leaf yield. However, most N is not utilized by the plant, negatively impacting the environment. To date, little is known regarding N utilization genes and mechanisms in the leaf production. To understand this, we investigated transcriptomes using RNA-seq and amino acid levels with N treatment in tea (Camellia sinensis), the most popular beverage crop. We identified 196 and 29 common differentially expressed genes in roots and leaves, respectively, in response to ammonium in two tea varieties. Among those genes, AMT, NRT and AQP for N uptake and GOGAT and GS for N assimilation were the key genes, validated by RT-qPCR, which expressed in a network manner with tissue specificity. Importantly, only AQP and three novel DEGs associated with stress, manganese binding, and gibberellin-regulated transcription factor were common in N responses across all tissues and varieties. A hypothesized gene regulatory network for N was proposed. A strong statistical correlation between key genes' expression and amino acid content was revealed. The key genes and regulatory network improve our understanding of the molecular mechanism of N usage and offer gene targets for plant improvement.
Single-trait and multi-trait genome-wide association analyses identify novel loci for blood pressure in African-ancestry populations
May 12, 2017   PLoS Genetics
Liang J, Le TH, Edwards DRV, Tayo BO, Gaulton KJ,   . . . . . .   , Rotimi C, Levy D, Chakravarti A, Zhu X, Franceschini N
Single-trait and multi-trait genome-wide association analyses identify novel loci for blood pressure in African-ancestry populations
May 12, 2017
PLoS Genetics
Hypertension is a leading cause of global disease, mortality, and disability. While individuals of African descent suffer a disproportionate burden of hypertension and its complications, they have been underrepresented in genetic studies. To identify novel susceptibility loci for blood pressure and hypertension in people of African ancestry, we performed both single and multiple-trait genome-wide association analyses. We analyzed 21 genome-wide association studies comprised of 31,968 individuals of African ancestry, and validated our results with additional 54,395 individuals from multi-ethnic studies. These analyses identified nine loci with eleven independent variants which reached genome-wide significance (P < 1.25×10-8) for either systolic and diastolic blood pressure, hypertension, or for combined traits. Single-trait analyses identified two loci (TARID/TCF21 and LLPH/TMBIM4) and multiple-trait analyses identified one novel locus (FRMD3) for blood pressure. At these three loci, as well as at GRP20/CDH17, associated variants had alleles common only in African-ancestry populations. Functional annotation showed enrichment for genes expressed in immune and kidney cells, as well as in heart and vascular cells/tissues. Experiments driven by these findings and using angiotensin-II induced hypertension in mice showed altered kidney mRNA expression of six genes, suggesting their potential role in hypertension. Our study provides new evidence for genes related to hypertension susceptibility, and the need to study African-ancestry populations in order to identify biologic factors contributing to hypertension.
Common genetic variation drives molecular heterogeneity in human iPSCs
May 10, 2017   Nature Add nature.com free-link Cancel
Kilpinen H, Goncalves A, Leha A, Afzal V, Alasoo K,   . . . . . .   , Vallier L, Watt FM, Durbin R, Stegle O, Gaffney DJ
Common genetic variation drives molecular heterogeneity in human iPSCs
May 10, 2017
Nature
Induced pluripotent stem cell (iPSC) technology has enormous potential to provide improved cellular models of human disease. However, variable genetic and phenotypic characterisation of many existing iPSC lines limits their potential use for research and therapy. Here, we describe the systematic generation, genotyping and phenotyping of 711 iPSC lines derived from 301 healthy individuals by the Human Induced Pluripotent Stem Cells Initiative (HipSci: http://www.hipsci.org). Our study outlines the major sources of genetic and phenotypic variation in iPSCs and establishes their suitability as models of complex human traits and cancer. Through genome-wide profiling we find that 5-46% of the variation in different iPSC phenotypes, including differentiation capacity and cellular morphology, arises from differences between individuals. Additionally, we assess the phenotypic consequences of rare, genomic copy number mutations that are repeatedly observed in iPSC reprogramming and present a comprehensive map of common regulatory variants affecting the transcriptome of human pluripotent cells.
Genomics pioneer gets its first drug
May 09, 2017   Nature Biotechnology Add nature.com free-link Cancel
Ratner M
De novo Sequencing and Transcriptome Analysis Reveal Key Genes Regulating Steroid Metabolism in Leaves, Roots, Adventitious Roots and Calli of Periploca sepium Bunge
May 09, 2017   Frontiers In Plant Science
Zhang J, Li X, Lu F, Wang S, An Y, Su X, Li X, Ma L, Han G
De novo Sequencing and Transcriptome Analysis Reveal Key Genes Regulating Steroid Metabolism in Leaves, Roots, Adventitious Roots and Calli of Periploca sepium Bunge
May 09, 2017
Frontiers In Plant Science
Periploca sepium Bunge is a traditional medicinal plant, whose root bark is important for Chinese herbal medicine. Its major bioactive compounds are C21 steroids and periplocin, a kind of cardiac glycoside, which are derived from the steroid synthesis pathway. However, research on P. sepium genome or transcriptomes and their related genes has been lacking for a long time. In this study we estimated this species nuclear genome size at 170 Mb (using flow cytometry). Then, RNA sequencing of four different tissue samples of P. sepium (leaves, roots, adventitious roots, and calli) was done using the sequencing platform Illumina/Solexa Hiseq 2,500. After de novo assembly and quantitative assessment, 90,375 all-transcripts and 71,629 all-unigenes were finally generated. Annotation efforts that used a number of public databases resulted in detailed annotation information for the transcripts. In addition, differentially expressed genes (DEGs) were identified by using digital gene profiling based on the reads per kilobase of transcript per million reads mapped (RPKM) values. Compared with the leaf samples (L), up-regulated genes and down-regulated genes were eventually obtained. To deepen our understanding of these DEGs, we performed two enrichment analyses: gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG). Here, the analysis focused upon the expression characteristics of those genes involved in the terpene metabolic pathway and the steroid biosynthesis pathway, to better elucidate the molecular mechanism of bioactive steroid synthesis in P. sepium. The bioinformatics analysis enabled us to find many genes that are involved in bioactive steroid biosynthesis. These genes encoded acetyl-CoA acetyltransferase (ACAT), HMG-CoA synthase (HMGS), HMG-CoA reductase (HMGR), mevalonate kinase (MK), phosphomevalonate kinase (PMK), mevalonate diphosphate decarboxylase (MDD), isopentenylpyrophosphate isomerase (IPPI), farnesyl pyrophosphate synthase (FPS), squalene synthase (SS), squalene epoxidase (SE), cycloartenol synthase (CAS), sterol C-24 methyltransferase (SMT1), sterol-4alpha-methyl oxidase 1 (SMO1), sterol 14alpha-demethylase (CYP51/14-SDM), delta(14)-sterol reductase (FK/14SR), C-8,7 sterol isomerase (HYD1), sterol-4alpha-methyl oxidase 2 (SMO2), delta(7)-sterol-C5(6)-desaturase (STE1/SC5DL), 7-dehydrocholesterol reductase (DWF5/DHCR7), delta (24)-sterol reductase (DWF1/DHCR24), sterol 22-desaturase (CYP710A), progesterone 5beta-reductase (5β-POR), 3-beta-hydroxysteroid dehydrogenase (3β-HSD). This research will be helpful to further understand the mechanism of bioactive steroid biosynthesis in P. sepium, namely C21 steroid and periplocin biosynthesis.
Maturation arrest in early postnatal sensory receptors by deletion of the miR-183/96/182 cluster in mouse
May 09, 2017   Proceedings Of The National Academy Of Sciences Of The United States Of America
Fan J, Jia L, Li Y, Ebrahim S, May-Simera H,   . . . . . .   , Qian H, Li T, Li W, Wistow G, Dong L
Maturation arrest in early postnatal sensory receptors by deletion of the miR-183/96/182 cluster in mouse
May 09, 2017
Proceedings Of The National Academy Of Sciences Of The United States Of America
The polycistronic miR-183/96/182 cluster is preferentially and abundantly expressed in terminally differentiating sensory epithelia. To clarify its roles in the terminal differentiation of sensory receptors in vivo, we deleted the entire gene cluster in mouse germline through homologous recombination. The miR-183/96/182 null mice display impairment of the visual, auditory, vestibular, and olfactory systems, attributable to profound defects in sensory receptor terminal differentiation. Maturation of sensory receptor precursors is delayed, and they never attain a fully differentiated state. In the retina, delay in up-regulation of key photoreceptor genes underlies delayed outer segment elongation and possibly mispositioning of cone nuclei in the retina. Incomplete maturation of photoreceptors is followed shortly afterward by early-onset degeneration. Cell biologic and transcriptome analyses implicate dysregulation of ciliogenesis, nuclear translocation, and an epigenetic mechanism that may control timing of terminal differentiation in developing photoreceptors. In both the organ of Corti and the vestibular organ, impaired terminal differentiation manifests as immature stereocilia and kinocilia on the apical surface of hair cells. Our study thus establishes a dedicated role of the miR-183/96/182 cluster in driving the terminal differentiation of multiple sensory receptor cells.
Obesity is associated with depot-specific alterations in adipocyte DNA methylation and gene expression
May 08, 2017   Adipocyte
Sonne SB, Yadav R, Yin G, Dalgaard MD, Myrmel LS, Gupta R, Wang J, Madsen L, Kajimura S, Kristiansen K
Obesity is associated with depot-specific alterations in adipocyte DNA methylation and gene expression
May 08, 2017
Adipocyte
The present study aimed to identify genes exhibiting concomitant obesity-dependent changes in DNA methylation and gene expression in adipose tissues in the mouse using diet-induced obese (DIO) C57BL/6J and genetically obese ob/ob mice as models. Mature adipocytes were isolated from epididymal and inguinal adipose tissues of ob/ob and DIO C57BL/6J mice. DNA methylation was analyzed by MeDIP-sequencing and gene expression by microarray analysis. The majority of differentially methylated regions (DMRs) were hypomethylated in obese mice. Global methylation of long interspersed elements indicated that hypomethylation did not reflect methyl donor deficiency. In both DIO and ob/ob mice, we observed more obesity-associated methylation changes in epididymal than in inguinal adipocytes. Assignment of DMRs to promoter, exon, intron and intergenic regions demonstrated that DIO-induced changes in DNA methylation in C57BL/6J mice occurred primarily in exons, whereas inguinal adipocytes of ob/ob mice exhibited a higher enrichment of DMRs in promoter regions than in other regions of the genome, suggesting an influence of leptin on DNA methylation in inguinal adipocytes. We observed altered methylation and expression of 9 genes in epididymal adipocytes, including the known obesity-associated genes, Ehd2 and Kctd15, and a novel candidate gene, Irf8, possibly involved in immune type 1/type2 balance. The use of 2 obesity models enabled us to dissociate changes associated with high fat feeding from those associated with obesity per se. This information will be of value in future studies on the mechanisms governing the development of obesity and changes in adipocyte function associated with obesity.
Genetic testing: The diagnostic power of RNA-seq
May 08, 2017   Nature Reviews. Genetics
Wrighton KH
Modeling Rett Syndrome Using TALEN-Edited MECP2 Mutant Cynomolgus Monkeys
May 19, 2017   Cell
Chen Y, Yu J, Niu Y, Qin D, Liu H,   . . . . . .   , Jiang T, Hu X, Ma Y, Ji W, Sun YE
Modeling Rett Syndrome Using TALEN-Edited MECP2 Mutant Cynomolgus Monkeys
May 19, 2017
Cell
Gene-editing technologies have made it feasible to create nonhuman primate models for human genetic disorders. Here, we report detailed genotypes and phenotypes of TALEN-edited MECP2 mutant cynomolgus monkeys serving as a model for a neurodevelopmental disorder, Rett syndrome (RTT), which is caused by loss-of-function mutations in the human MECP2 gene. Male mutant monkeys were embryonic lethal, reiterating that RTT is a disease of females. Through a battery of behavioral analyses, including primate-unique eye-tracking tests, in combination with brain imaging via MRI, we found a series of physiological, behavioral, and structural abnormalities resembling clinical manifestations of RTT. Moreover, blood transcriptome profiling revealed that mutant monkeys resembled RTT patients in immune gene dysregulation. Taken together, the stark similarity in phenotype and/or endophenotype between monkeys and patients suggested that gene-edited RTT founder monkeys would be of value for disease mechanistic studies as well as development of potential therapeutic interventions for RTT. Copyright © 2017 Elsevier Inc. All rights reserved.
Integrating Results across Methodologies Is Essential for Producing Robust Neuronal Taxonomies
May 18, 2017   Neuron
Cembrowski MS, Spruston N
Integrating Results across Methodologies Is Essential for Producing Robust Neuronal Taxonomies
May 18, 2017
Neuron
Elucidating the diversity and spatial organization of cell types in the brain is an essential goal of neuroscience, with many emerging technologies helping to advance this endeavor. Using a new in situ hybridization method that can measure the expression of hundreds of genes in a given mouse brain section (amplified seqFISH), Shah et al. (2016) describe a spatial organization of hippocampal cell types that differs from previous reports. In seeking to understand this discrepancy, we find that many of the barcoded genes used by seqFISH to characterize this spatial organization, when cross-validated by other sensitive methodologies, exhibit negligible expression in the hippocampus. Additionally, the results of Shah et al. (2016) do not recapitulate canonical cellular hierarchies and improperly classify major neuronal cell types. We suggest that, when describing the spatial organization of brain regions, cross-validation using multiple techniques should be used to yield robust and informative cellular classification. This Matters Arising paper is in response to Shah et al. (2016), published in Neuron. See also the response by Shah et al. (2017), published in this issue. Copyright © 2017 Elsevier Inc. All rights reserved.
Polygenic transmission disequilibrium confirms that common and rare variation act additively to create risk for autism spectrum disorders
May 15, 2017   Nature Genetics Add nature.com free-link Cancel
Weiner DJ, Wigdor EM, Ripke S, Walters RK, Kosmicki JA,   . . . . . .   , Mortensen PB, Børglum AD, Smith GD, Daly MJ, Robinson EB
Polygenic transmission disequilibrium confirms that common and rare variation act additively to create risk for autism spectrum disorders
May 15, 2017
Nature Genetics
Autism spectrum disorder (ASD) risk is influenced by common polygenic and de novo variation. We aimed to clarify the influence of polygenic risk for ASD and to identify subgroups of ASD cases, including those with strongly acting de novo variants, in which polygenic risk is relevant. Using a novel approach called the polygenic transmission disequilibrium test and data from 6,454 families with a child with ASD, we show that polygenic risk for ASD, schizophrenia, and greater educational attainment is over-transmitted to children with ASD. These findings hold independent of proband IQ. We find that polygenic variation contributes additively to risk in ASD cases who carry a strongly acting de novo variant. Lastly, we show that elements of polygenic risk are independent and differ in their relationship with phenotype. These results confirm that the genetic influences on ASD are additive and suggest that they create risk through at least partially distinct etiologic pathways.
Recurrent noncoding regulatory mutations in pancreatic ductal adenocarcinoma
May 08, 2017   Nature Genetics Add nature.com free-link Cancel
Feigin ME, Garvin T, Bailey P, Waddell N, Chang DK,   . . . . . .   , Khurana E, Stein LD, Biankin AV, Schatz MC, Tuveson DA
Recurrent noncoding regulatory mutations in pancreatic ductal adenocarcinoma
May 08, 2017
Nature Genetics
The contributions of coding mutations to tumorigenesis are relatively well known; however, little is known about somatic alterations in noncoding DNA. Here we describe GECCO (Genomic Enrichment Computational Clustering Operation) to analyze somatic noncoding alterations in 308 pancreatic ductal adenocarcinomas (PDAs) and identify commonly mutated regulatory regions. We find recurrent noncoding mutations to be enriched in PDA pathways, including axon guidance and cell adhesion, and newly identified processes, including transcription and homeobox genes. We identified mutations in protein binding sites correlating with differential expression of proximal genes and experimentally validated effects of mutations on expression. We developed an expression modulation score that quantifies the strength of gene regulation imposed by each class of regulatory elements, and found the strongest elements were most frequently mutated, suggesting a selective advantage. Our detailed single-cancer analysis of noncoding alterations identifies regulatory mutations as candidates for diagnostic and prognostic markers, and suggests new mechanisms for tumor evolution.
Ustilago maydis effectors and their impact on virulence
May 08, 2017   Nature Reviews. Microbiology
Lanver D, Tollot M, Schweizer G, Lo Presti L, Reissmann S, Ma LS, Schuster M, Tanaka S, Liang L, Ludwig N, Kahmann R
Ustilago maydis effectors and their impact on virulence
May 08, 2017
Nature Reviews. Microbiology
Biotrophic fungal plant pathogens establish an intimate relationship with their host to support the infection process. Central to this strategy is the secretion of a range of protein effectors that enable the pathogen to evade plant immune defences and modulate host metabolism to meet its needs. In this Review, using the smut fungus Ustilago maydis as an example, we discuss new insights into the effector repertoire of smut fungi that have been gained from comparative genomics and discuss the molecular mechanisms by which U. maydis effectors change processes in the plant host. Finally, we examine how the expression of effector genes and effector secretion are coordinated with fungal development in the host.
Integrative analysis of genomic sequencing data reveals higher prevalence of LRP1B mutations in lung adenocarcinoma patients with COPD
May 19, 2017   Scientific Reports
Xiao D, Li F, Pan H, Liang H, Wu K, He J
Integrative analysis of genomic sequencing data reveals higher prevalence of LRP1B mutations in lung adenocarcinoma patients with COPD
May 19, 2017
Scientific Reports
Both chronic Obstruction Pulmonary Disease (COPD) and lung cancer are leading causes of death globally. Although COPD and lung cancer coexist frequently, it is unknown whether lung cancer patients with COPD harbor distinct genomic characteristics compared to those without COPD. In this study, we retrospectively analyzed genomic sequencing data from 272 patients with lung adenocarcinoma (LUAD) and compared the genetic alterations in LUAD patients with and without COPD. Integrative analysis of whole-genome and exome sequencing data revealed that COPD and non-COPD groups showed high concordance in mutational burden and spectra. Notably, we also found that EGFR mutations were more prevalent in LUAD patients without COPD, whereas mutated LRP1B was more frequently observed in LUAD patients with COPD. In addition, multi-variable analysis with logistic regression demonstrated that mutation of LRP1B was a predictive marker for the presence of COPD in the patients with LUAD. Our analysis demonstrated for the first time the high concordance in genomic alterations between the tumors from LUAD patients with and without COPD. We also identified higher prevalence of LRP1B among the LUAD patients with COPD, which might help understand the underlying mechanisms which link COPD and lung cancer.
Somatic Tumor Mutations Detected by Targeted Next Generation Sequencing in Minute Amounts of Serum-Derived Cell-Free DNA
May 19, 2017   Scientific Reports
Weerts MJA, van Marion R, Helmijr JCA, Beaufort CM, Krol NMG, Trapman-Jansen AMAC, Dinjens WNM, Sleijfer S, Jansen MPHM, Martens JWM
Somatic Tumor Mutations Detected by Targeted Next Generation Sequencing in Minute Amounts of Serum-Derived Cell-Free DNA
May 19, 2017
Scientific Reports
The use of blood-circulating cell-free DNA (cfDNA) as 'liquid-biopsy' is explored worldwide, with hopes for its potential in providing prognostic or predictive information in cancer treatment. In exploring cfDNA, valuable repositories are biobanks containing material collected over time, however these retrospective cohorts have restrictive resources. In this study, we aimed to detect tumor-specific mutations in only minute amounts of serum-derived cfDNA by using a targeted next generation sequencing (NGS) approach. In a retrospective cohort of ten metastatic breast cancer patients, we profiled DNA from primary tumor tissue (frozen), tumor-adjacent normal tissue (formalin-fixed paraffin embedded), and three consecutive serum samples (frozen). Our presented workflow includes comparisons with matched normal DNA or in silico reference DNA to discriminate germline from somatic variants, validation of variants through the detection in at least two DNA samples of an individual, and the use of public databases on variants. By our workflow, we were able to detect a total of four variants traceable as circulating tumor DNA (ctDNA) in the sera of three of the ten patients.
Inhibition of endocytic lipid antigen presentation by common lipophilic environmental pollutants
May 19, 2017   Scientific Reports
Sharma M, Zhang X, Zhang S, Niu L, Ho SM, Chen A, Huang S
Inhibition of endocytic lipid antigen presentation by common lipophilic environmental pollutants
May 19, 2017
Scientific Reports
Environmental pollutants as non-heritable factors are now recognized as triggers for multiple human inflammatory diseases involving T cells. We postulated that lipid antigen presentation mediated by cluster of differentiation 1 (CD1) proteins for T cell activation is susceptible to lipophilic environmental pollutants. To test this notion, we determined whether the common lipophilic pollutants benzo[a]pyrene and diesel exhaust particles impact on the activation of lipid-specific T cells. Our results demonstrated that the expression of CD1a and CD1d proteins, and the activation of CD1a- and CD1d-restricted T cells were sensitively inhibited by benzo[a]pyrene even at the low concentrations detectable in exposed human populations. Similarly, diesel exhaust particles showed a marginal inhibitory effect. Using transcriptomic profiling, we discovered that the gene expression for regulating endocytic and lipid metabolic pathways was perturbed by benzo[a]pyrene. Imaging flow cytometry also showed that CD1a and CD1d proteins were retained in early and late endosomal compartments, respectively, supporting an impaired endocytic lipid antigen presentation for T cell activation upon benzo[a]pyrene exposure. This work conceptually demonstrates that lipid antigen presentation for T cell activation is inhibited by lipophilic pollutants through profound interference with gene expression and endocytic function, likely further disrupting regulatory cytokine secretion and ultimately exacerbating inflammatory diseases.
Phosphoserine aminotransferase 1 is associated to poor outcome on tamoxifen therapy in recurrent breast cancer
May 19, 2017   Scientific Reports
De Marchi T, Timmermans MA, Sieuwerts AM, Smid M, Look MP, Grebenchtchikov N, Sweep FCGJ, Smits JG, Magdolen V, van Deurzen CHM, Foekens JA, Umar A, Martens JW
Phosphoserine aminotransferase 1 is associated to poor outcome on tamoxifen therapy in recurrent breast cancer
May 19, 2017
Scientific Reports
In a previous study, we detected a significant association between phosphoserine aminotransferase 1 (PSAT1) hyper-methylation and mRNA levels to outcome to tamoxifen treatment in recurrent disease. We here aimed to study the association of PSAT1 protein levels to outcome upon tamoxifen treatment and to obtain more insight in its role in tamoxifen resistance. A cohort of ER positive, hormonal therapy naïve primary breast carcinomas was immunohistochemically (IHC) stained for PSAT1. Staining was analyzed for association with patient's time to progression (TTP) and overall response on first-line tamoxifen for recurrent disease. PSAT1 mRNA levels were also assessed by reverse transcriptase quantitative polymerase chain reaction (RT-qPCR; n = 161) and Affymetrix GeneChip (n = 155). Association of PSAT1 to biological pathways on tamoxifen outcome were assessed by global test. PSAT1 protein and mRNA levels were significantly associated to poor outcome to tamoxifen treatment. When comparing PSAT1 protein and mRNA levels, IHC and RT-qPCR data showed a significant association. Global test results showed that cytokine and JAK-STAT signaling were associated to PSAT1 expression. We hereby report that PSAT1 protein and mRNA levels measured in ER positive primary tumors are associated with poor clinical outcome to tamoxifen.

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