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Genetics
Chinese Norms for the Autism Spectrum Rating Scale
Feb 24, 2017   Neuroscience Bulletin
Zhou H, Zhang L, Zou X, Luo X, Xia K, Wu L, Wang Y, Xu X, Ge X, Jiang YH, Fombonne E, Yan W, Wang Y
Chinese Norms for the Autism Spectrum Rating Scale
Feb 24, 2017
Neuroscience Bulletin
This study aimed to establish norms for the modified Chinese version of the Autism Spectrum Rating Scale (ASRS). Participants were recruited from Shanghai, Harbin, Guangzhou, and Changsha, China, and their parents and teachers were invited to complete the Chinese Parent version and the Teacher version of the ASRS. In both versions, boys had significantly higher sub-scale scores and total score (T-score) by 1-3 and 4-5 points respectively, than girls (both P 
ETV Transcriptional Upregulation is More Reliable Than RNA Sequencing Algorithms and FISH in Diagnosing Round Cell Sarcomas with CIC Gene Rearrangements
Feb 24, 2017   Genes, Chromosomes & Cancer
Kao YC, Sung YS, Chen CL, Zhang L, Dickson BC, Swanson D, Vaiyapuri S, Latif F, Alholle A, Huang SC, Hornick JL, Antonescu CR
ETV Transcriptional Upregulation is More Reliable Than RNA Sequencing Algorithms and FISH in Diagnosing Round Cell Sarcomas with CIC Gene Rearrangements
Feb 24, 2017
Genes, Chromosomes & Cancer
CIC rearrangements have been reported in two-thirds of EWSR1-negative small blue round cell tumors (SBRCTs). However, a number of SBRCTs remain unclassified despite exhaustive analysis. We collected 14 SBRCTs lacking driver genetic events by RNA sequencing (RNAseq) analysis. Unsupervised hierarchical clustering was performed using samples from our RNAseq database, including 13 SBRCTs with non-CIC genetic abnormalities and 2 CIC-rearranged angiosarcomas among others. Remarkably, all 14 study cases showed high mRNA levels of ETV1/4/5, and by unsupervised clustering most grouped into a distinct cluster, separate from other tumors. Based on these results indicating a close relationship with CIC-rearranged tumors, we manually inspected CIC reads in RNAseq data. FISH for CIC and DUX4 abnormalities and immunohistochemical stains for ETV4 were also performed. In the control group, only 2 CIC-rearranged angiosarcomas had high ETV1/4/5 expression. Upon manual inspection of CIC traces, 7 of 14 cases showed CIC-DUX4 fusion reads, 2 cases had DUX4-CIC reads, while the remaining 5 were negative. FISH showed CIC break-apart in 7 cases, including 5 cases lacking CIC-DUX4 or DUX4-CIC fusion reads on RNAseq manual inspection. However, no CIC abnormalities were detected by FISH in 6 cases with CIC-DUX4 or DUX4-CIC reads. ETV4 immunoreactivity was positive in 7 of 11 cases. Our results highlight the underperformance of FISH and RNAseq methods in diagnosing SBRCTs with CIC gene abnormalities. The downstream ETV1/4/5 transcriptional up-regulation appears highly sensitive and specific and can be used as a reliable molecular signature and diagnostic method for CIC fusion positive SBRCTs. This article is protected by copyright. All rights reserved.© 2017 Wiley Periodicals, Inc.
Construction of Plastid Expression Vector and Development of Genetic Transformation System for the Seaweed Pyropia yezoensis
Feb 24, 2017   Marine Biotechnology (New York, N.Y.)
Kong F, Zhao H, Liu W, Li N, Mao Y
Construction of Plastid Expression Vector and Development of Genetic Transformation System for the Seaweed Pyropia yezoensis
Feb 24, 2017
Marine Biotechnology (New York, N.Y.)
Pyropia yezoensis, belonging to the Rhodophyta, is an economically important seaweed. In this study, we developed a high-efficiency plastid transformation platform for P. yezoensis. In the plastid transformation vector, psbA UTR of P. yezoensis, including the promoter and 3' UTR, was used to express foreign genes. The integration site was a transcriptionally active intergenic region between the rrsB and trnI genes, located in the inverted repeat regions of the plastid genome. The CAT and eGFP genes were integrated into the plastid genome at this site. The expression of CAT in the transformants confers resistance to chloramphenicol through the action of chloramphenicol acetyltransferase, which inactivates the drug, thereby allowing the plant to grow well under selective pressure. The eGFP fluorescence signal was also observed in transformed cells and the transformants. The average survival rate of treated cells was estimated to be approximately 4.2‰ (4 transplastomic colonies per 1000 gametophyte cells). Multiple-PCR analyses confirmed that the CAT and eGFP genes were successfully integrated in the site between rrsB and trnI. Western blot also showed eGFP expression in the cells of transformants. Thus, this study presents the first convenient plastid gene expression system for P. yezoensis and provides an important platform for studying gene function in P. yezoensis.
Scaffolding bacterial genomes and probing host-virus interactions in gut microbiome by proximity ligation (chromosome capture) assay
Feb 24, 2017   Science Advances
Marbouty M, Baudry L, Cournac A, Koszul R
Scaffolding bacterial genomes and probing host-virus interactions in gut microbiome by proximity ligation (chromosome capture) assay
Feb 24, 2017
Science Advances
The biochemical activities of microbial communities, or microbiomes, are essential parts of environmental and animal ecosystems. The dynamics, balance, and effects of these communities are strongly influenced by phages present in the population. Being able to characterize bacterium-phage relationships is therefore essential to investigate these ecosystems to the full extent of their complexity. However, this task is currently limited by (i) the ability to characterize complete bacterial and viral genomes from a complex mix of species and (ii) the difficulty to assign phage sequences to their bacterial hosts. We show that both limitations can be circumvented using meta3C, an experimental and computational approach that exploits the physical contacts between DNA molecules to infer their proximity. In a single experiment, dozens of bacterial and phage genomes present in a complex mouse gut microbiota were assembled and scaffolded de novo. The phage genomes were then assigned to their putative bacterial hosts according to the physical contacts between the different DNA molecules, opening new perspectives for a comprehensive picture of the genomic structure of the gut flora. Therefore, this work holds far-reaching implications for human health studies aiming to bridge the virome to the microbiome.
Age-associated molecular changes are deleterious and may modulate life span through diet
Feb 24, 2017   Science Advances
Lee SG, Kaya A, Avanesov AS, Podolskiy DI, Song EJ, Go DM, Jin GD, Hwang JY, Kim EB, Kim DY, Gladyshev VN
Age-associated molecular changes are deleterious and may modulate life span through diet
Feb 24, 2017
Science Advances
Transition through life span is accompanied by numerous molecular changes, such as dysregulated gene expression, altered metabolite levels, and accumulated molecular damage. These changes are thought to be causal factors in aging; however, because they are numerous and are also influenced by genotype, environment, and other factors in addition to age, it is difficult to characterize the cumulative effect of these molecular changes on longevity. We reasoned that age-associated changes, such as molecular damage and tissue composition, may influence life span when used in the diet of organisms that are closely related to those that serve as a dietary source. To test this possibility, we used species-specific culture media and diets that incorporated molecular extracts of young and old organisms and compared the influence of these diets on the life span of yeast, fruitflies, and mice. In each case, the "old" diet or medium shortened the life span for one or both sexes. These findings suggest that age-associated molecular changes, such as cumulative damage and altered dietary composition, are deleterious and causally linked with aging and may affect life span through diet.
Induced Pluripotent Stem Cell-Derived Endothelial Cells Overexpressing Interleukin-8 Receptors A/B and/or C-C Chemokine Receptors 2/5 Inhibit Vascular Injury Response
Feb 24, 2017   Stem Cells Translational Medicine
Giordano S, Zhao X, Chen YF, Litovsky SH, Hage FG, Townes TM, Sun CW, Wu LC, Oparil S, Xing D
Induced Pluripotent Stem Cell-Derived Endothelial Cells Overexpressing Interleukin-8 Receptors A/B and/or C-C Chemokine Receptors 2/5 Inhibit Vascular Injury Response
Feb 24, 2017
Stem Cells Translational Medicine
Recruitment of neutrophils and monocytes/macrophages to the site of vascular injury is mediated by binding of chemoattractants to interleukin (IL) 8 receptors RA and RB (IL8RA/B) C-C chemokine receptors (CCR) 2 and 5 expressed on neutrophil and monocyte/macrophage membranes. Endothelial cells (ECs) derived from rat-induced pluripotent stem cells (RiPS) were transduced with adenovirus containing cDNA of IL8RA/B and/or CCR2/5. We hypothesized that RiPS-ECs overexpressing IL8RA/B (RiPS-IL8RA/B-ECs), CCR2/5 (RiPS-CCR2/5-ECs), or both receptors (RiPS-IL8RA/B+CCR2/5-ECs) will inhibit inflammatory responses and neointima formation in balloon-injured rat carotid artery. Twelve-week-old male Sprague-Dawley rats underwent balloon injury of the right carotid artery and intravenous infusion of (a) saline vehicle, (b) control RiPS-Null-ECs (ECs transduced with empty virus), (c) RiPS-IL8RA/B-ECs, (d) RiPS-CCR2/5-ECs, or (e) RiPS-IL8RA/B+CCR2/5-ECs. Inflammatory mediator expression and leukocyte infiltration were measured in injured and uninjured arteries at 24 hours postinjury by enzyme-linked immunosorbent assay (ELISA) and immunohistochemistry, respectively. Neointima formation was assessed at 14 days postinjury. RiPS-ECs expressing the IL8RA/B or CCR2/5 homing device targeted the injured arteries and decreased injury-induced inflammatory cytokine expression, neutrophil/macrophage infiltration, and neointima formation. Transfused RiPS-ECs overexpressing IL8RA/B and/or CCR2/5 prevented inflammatory responses and neointima formation after vascular injury. Targeted delivery of iPS-ECs with a homing device to inflammatory mediators in injured arteries provides a novel strategy for the treatment of cardiovascular diseases. © Stem Cells Translational Medicine 2016.© 2016 The Authors Stem Cells Translational Medicine published by Wiley Periodicals, Inc. on behalf of AlphaMed Press.
RD26 mediates crosstalk between drought and brassinosteroid signalling pathways
Feb 24, 2017   Nature Communications
Ye H, Liu S, Tang B, Chen J, Xie Z,   . . . . . .   , Li Z, Aluru M, Aluru S, Schnable PS, Yin Y
RD26 mediates crosstalk between drought and brassinosteroid signalling pathways
Feb 24, 2017
Nature Communications
Brassinosteroids (BRs) regulate plant growth and stress responses via the BES1/BZR1 family of transcription factors, which regulate the expression of thousands of downstream genes. BRs are involved in the response to drought, however the mechanistic understanding of interactions between BR signalling and drought response remains to be established. Here we show that transcription factor RD26 mediates crosstalk between drought and BR signalling. When overexpressed, BES1 target gene RD26 can inhibit BR-regulated growth. Global gene expression studies suggest that RD26 can act antagonistically to BR to regulate the expression of a subset of BES1-regulated genes, thereby inhibiting BR function. We show that RD26 can interact with BES1 protein and antagonize BES1 transcriptional activity on BR-regulated genes and that BR signalling can also repress expression of RD26 and its homologues and inhibit drought responses. Our results thus reveal a mechanism coordinating plant growth and drought tolerance.
Bipolar disorder risk gene
Feb 24, 2017   Journal Of Psychiatry & Neuroscience : JPN
Shenker JJ, Sengupta SM, Joober R, Malla A, Chakravarty MM, Lepage M
Bipolar disorder risk gene
Feb 24, 2017
Journal Of Psychiatry & Neuroscience : JPN
BACKGROUND: Despite being diagnostically associated uniquely with schizophrenia, negative symptoms are also observed in bipolar disorder (BD). Genome-wide association studies (GWAS) have uncovered a number of shared risk genes between schizophrenia and BD. The objectives of this study were to examine whether previously identified risk genes for BD are associated with negative symptom severity within a first-episode schizophrenia (FES) cohort and to examine whether such genes influence brain morphology. METHODS: Patients experiencing FES were genotyped for 21 previously identified BD risk genes; a series of univariate analyses of covariance examined the association between negative symptom severity, as measured using the Scale for the Assessment of Negative Symptoms (SANS), and genotype. A subset of participants underwent a structural 1.5 T MRI RESULTS: We included 133 patients with FES in our analysis; 61 of them underwent structural MRI. We observed a significant association between negative symptom severity and the BD risk gene LIMITATIONS: Limitations of this study include its modest sample size and lack of a control sample. CONCLUSION: Lacking the
Epigenetics studies of fetal alcohol spectrum disorder: where are we now?
Feb 24, 2017   Epigenomics
Lussier AA, Weinberg J, Kobor MS
Epigenetics studies of fetal alcohol spectrum disorder: where are we now?
Feb 24, 2017
Epigenomics
Adverse in utero events can alter the development and function of numerous physiological systems, giving rise to lasting neurodevelopmental deficits. In particular, data have shown that prenatal alcohol exposure can reprogram neurobiological systems, altering developmental trajectories and resulting in increased vulnerability to adverse neurobiological, behavioral and health outcomes. Increasing evidence suggests that epigenetic mechanisms are potential mediators for the reprogramming of neurobiological systems, as they may provide a link between the genome, environmental conditions and neurodevelopmental outcomes. This review outlines the current state of epigenetic research in fetal alcohol spectrum disorder, highlighting the role of epigenetic mechanisms in the reprogramming of neurobiological systems by alcohol and as potential diagnostic tools for fetal alcohol spectrum disorder. We also present an assessment of the current limitations in studies of prenatal alcohol exposure, and highlight the future steps needed in the field.
Comparative transcriptomic analysis reveals the roles of overlapping heat-/drought-responsive genes in poplars exposed to high temperature and drought
Feb 24, 2017   Scientific Reports
Jia J, Zhou J, Shi W, Cao X, Luo J, Polle A, Luo ZB
Comparative transcriptomic analysis reveals the roles of overlapping heat-/drought-responsive genes in poplars exposed to high temperature and drought
Feb 24, 2017
Scientific Reports
High temperature (HT) and drought are both critical factors that constrain tree growth and survival under global climate change, but it is surprising that the transcriptomic reprogramming and physiological relays involved in the response to HT and/or drought remain unknown in woody plants. Thus, Populus simonii saplings were exposed to either ambient temperature or HT combined with sufficient watering or drought. RNA-sequencing analysis showed that a large number of genes were differentially expressed in poplar roots and leaves in response to HT and/or desiccation, but only a small number of these genes were identified as overlapping heat-/drought-responsive genes that are mainly involved in RNA regulation, transport, hormone metabolism, and stress. Furthermore, the overlapping heat-/drought-responsive genes were co-expressed and formed hierarchical genetic regulatory networks under each condition compared. HT-/drought-induced transcriptomic reprogramming is linked to physiological relays in poplar roots and leaves. For instance, HT- and/or drought-induced abscisic acid accumulation and decreases in auxin and other phytohormones corresponded well with the differential expression of a few genes involved in hormone metabolism. These results suggest that overlapping heat-/drought-responsive genes will play key roles in the transcriptional and physiological reconfiguration of poplars to HT and/or drought under future climatic scenarios.
Increased 4R tau expression and behavioural changes in a novel MAPT-N296H genomic mouse model of tauopathy
Feb 24, 2017   Scientific Reports
Wobst HJ, Denk F, Oliver PL, Livieratos A, Taylor TN, Knudsen MH, Bengoa-Vergniory N, Bannerman D, Wade-Martins R
Increased 4R tau expression and behavioural changes in a novel MAPT-N296H genomic mouse model of tauopathy
Feb 24, 2017
Scientific Reports
The microtubule-associated protein tau is implicated in various neurodegenerative diseases including Alzheimer's disease, progressive supranuclear palsy and corticobasal degeneration, which are characterized by intracellular accumulation of hyperphosphorylated tau. Mutations in the tau gene MAPT cause frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17). In the human central nervous system, six tau isoforms are expressed, and imbalances in tau isoform ratios are associated with pathology. To date, few animal models of tauopathy allow for the potential influence of these protein isoforms, relying instead on cDNA-based transgene expression. Using the P1-derived artificial chromosome (PAC) technology, we created mouse lines expressing all six tau isoforms from the human MAPT locus, harbouring either the wild-type sequence or the disease-associated N296H mutation on an endogenous Mapt-/- background. Animals expressing N296H mutant tau recapitulated early key features of tauopathic disease, including a tau isoform imbalance and tau hyperphosphorylation in the absence of somatodendritic tau inclusions. Furthermore, N296H animals displayed behavioural anomalies such as hyperactivity, increased time in the open arms of the elevated plus maze and increased immobility during the tail suspension test. The mouse models described provide an excellent model to study the function of wild-type or mutant tau in a highly physiological setting.
Clinical and Molecular Assessment in a Female with Fragile X Syndrome and Tuberous Sclerosis
Feb 24, 2017   Journal Of Genetic Disorders & Genetic Reports
Yrigollen CM, Pacini L, Nobile V, Lozano R, Hagerman RJ, Bagni C, Tassone F
Clinical and Molecular Assessment in a Female with Fragile X Syndrome and Tuberous Sclerosis
Feb 24, 2017
Journal Of Genetic Disorders & Genetic Reports
OBJECTIVE: Fragile X syndrome (FXS) and tuberous sclerosis (TSC) are genetic disorders that result in intellectual disability and an increased prevalence of autism spectrum disorders (ASD). While the clinical presentation of each disorder is distinct, the molecular causes are linked to a disruption in the mTORC1 (mammalian Target of Rapamycin Complex 1) and ERK1/2 (Extracellular signal-Regulated Kinase) signaling pathways. METHODS: We assessed the clinical and molecular characteristics of an individual seen at the UC Davis MIND Institute with a diagnosis of FXS and TSC. Clinical evaluation of physical, behavioral, and cognitive impairments were performed. Additionally, total and phosphorylated proteins along the mTORC1 and ERK1/2 pathways were measured in primary fibroblast cell lines from the proband. RESULTS: In this case the phenotypic effects that result in a human with both FXS and TSC are shown to be severe. Changes in mTORC1 and ERK1/2 signaling proteins and global protein synthesis were not found to be noticeably different between four cohorts (typically developing, CONCLUSION: It has previously been suggested that disruption of the mTORC1 pathway was reciprocal in TSC and FXS double knock-out mouse models so that the regulation of these pathways were more similar to wild-type mice compared to mice harboring a
Feb 24, 2017   Frontiers In Plant Science
Chi Y, Wang T, Xu G, Yang H, Zeng X, Shen Y, Yu D, Huang F
Feb 24, 2017
Frontiers In Plant Science
MADS-domain proteins are important transcription factors involved in many aspects of plant reproductive development. In this study, a MADS-box gene,
Ceftaroline-Resistant, Daptomycin-Tolerant, and Heterogeneous Vancomycin-Intermediate Methicillin-Resistant Staphylococcus aureus Causing Infective Endocarditis
Feb 24, 2017   Antimicrobial Agents And Chemotherapy
Nigo M, Diaz L, Carvajal LP, Tran TT, Rios R, Panesso D, Garavito JD, Miller WR, Wanger A, Weinstock G, Munita JM, Arias CA, Chambers HF
Ceftaroline-Resistant, Daptomycin-Tolerant, and Heterogeneous Vancomycin-Intermediate Methicillin-Resistant Staphylococcus aureus Causing Infective Endocarditis
Feb 24, 2017
Antimicrobial Agents And Chemotherapy
We report a case of infective endocarditis (IE) caused by ceftaroline-resistant, daptomycin-tolerant, and heterogeneous vancomycin-intermediate methicillin-resistant Copyright © 2017 American Society for Microbiology.
Inhibition of Virulence-promoting Disulfide Bond Formation Enzyme DsbB is blocked by Mutating Residues in two distinct regions
Feb 24, 2017   The Journal Of Biological Chemistry
Landeta C, Meehan BM, McPartland L, Ingendahl L, Hatahet F, Tran NQ, Boyd D, Beckwith J
Inhibition of Virulence-promoting Disulfide Bond Formation Enzyme DsbB is blocked by Mutating Residues in two distinct regions
Feb 24, 2017
The Journal Of Biological Chemistry
Disulfide bonds contribute to protein stability, activity and folding in a variety of proteins including many involved in bacterial virulence such as, toxins, adhesins, flagella and pili among others. Therefore, inhibitors of disulfide bond formation enzymes could have profound effects on pathogen virulence. In the Escherichia coli disulfide bond formation pathway, the periplasmic protein DsbA introduces disulfide bonds into substrates and then the cytoplasmic membrane protein DsbB reoxidizes DsbAs cysteines regenerating its activity. Thus, DsbB generates a protein disulfide bond de novo by transferring electrons to the quinone pool. We previously identified an effective pyridazinone-related inhibitor of DsbB enzymes from several gram-negative bacteria. In order to map the protein residues that are important for the interaction with this inhibitor, we randomly mutagenized by error-prone PCR the E. coli dsbB gene and selected dsbB mutants that confer resistance to this drug using two approaches. We characterized in vivo and in vitro some of these mutants that map to two areas in the structure of DsbB, one located between the two first transmembrane segments where the quinone ring binds and the other located in the second periplasmic loop of DsbB, which interacts with DsbA. In addition, we show that a mutant version of a protein involved in lipopolysaccharide assembly, lptD4213, is synthetically lethal with the deletion of dsbB as well as with DsbB inhibitors. This finding suggests that drugs decreasing LptD assembly may be synthetically lethal with inhibitors of the Dsb pathway, potentiating antibiotic effects.Copyright © 2017, The American Society for Biochemistry and Molecular Biology.
Yeast models of Parkinson's disease-associated molecular pathologies
Feb 24, 2017   Current Opinion In Genetics & Development
Tenreiro S, Franssens V, Winderickx J, Outeiro TF
Yeast models of Parkinson's disease-associated molecular pathologies
Feb 24, 2017
Current Opinion In Genetics & Development
The aging of the human population is resulting in an increase in the number of people afflicted by neurodegenerative disorders such as Parkinson's disease (PD), creating tremendous socio-economic challenges. This requires the urgent for the development of effective therapies, and of tools for early diagnosis of the disease. However, our understanding of the molecular mechanisms underlying PD pathogenesis is still incomplete, hampering progress in those areas. In recent years, the progression made in genetics has considerably contributed to our knowledge, by identifying several novel PD genes. Furthermore, many cellular and animal models have proven their value to decipher pathways involved in PD development. In this review we highlight the value of the yeast Saccharomyces cerevisiae as a model for PD. This unicellular eukaryote has contributed to our understanding of the cellular mechanisms targeted by most important PD genes and offers an excellent tool for discovering novel players via powerful and informative high throughput screens that accelerate further validation in more complex models.Copyright © 2017 Elsevier Ltd. All rights reserved.
Improving data availability for brain image biobanking in healthy subjects: practice-based suggestions from an international multidisciplinary working group
Feb 24, 2017   NeuroImage
BRAINS (Brain Imaging in Normal Subjects) Expert Working Group, Shenkin SD, Pernet C, Nichols TE, Poline JB,   . . . . . .   , Anblagan D, Job DE, Alexander Dickie D, Rodriguez D, Wardlaw JM
Improving data availability for brain image biobanking in healthy subjects: practice-based suggestions from an international multidisciplinary working group
Feb 24, 2017
NeuroImage
Brain imaging is now ubiquitous in clinical practice and research. The case for bringing together large amounts of image data from well-characterised healthy subjects and those with a range of common brain diseases across the life course is now compelling. This report follows a meeting of international experts from multiple disciplines, all interested in brain image biobanking. The meeting included neuroimaging experts (clinical and non-clinical), computer scientists, epidemiologists, clinicians, ethicists, and lawyers involved in creating brain image banks. The meeting followed a structured format to discuss current and emerging brain image banks; applications such as atlases; conceptual and statistical problems (e.g. defining 'normality'); legal, ethical and technological issues (e.g. consents, potential for data linkage, data security, harmonisation, data storage and enabling of research data sharing). We summarise the lessons learned from the experiences of a wide range of individual image banks, and provide practical recommendations to enhance creation, use and reuse of neuroimaging data. Our aim is to maximise the benefit of the image data, provided voluntarily by research participants and funded by many organisations, for human health. Our ultimate vision is of a federated network of brain image biobanks accessible for large studies of brain structure and function.Copyright © 2017. Published by Elsevier Inc.
Histone H1 defect in escort cells triggers germline tumor in Drosophila ovary
Feb 24, 2017   Developmental Biology
Yang Z, Sun J, Hu Y, Wang F, Wang X,   . . . . . .   , Li H, Chang Z, Liu LP, Liu Q, Ni JQ
Histone H1 defect in escort cells triggers germline tumor in Drosophila ovary
Feb 24, 2017
Developmental Biology
Drosophila ovary is recognized as one of the best model systems to study stem cell biology in vivo. We had previously identified an autonomous role of the histone H1 in germline stem cell (GSC) maintenance. Here, we found that histone H1 depletion in escort cells (ECs) resulted in an increase of spectrosome-containing cells (SCCs), an ovary tumor-like phenotype. Further analysis showed that the Dpp pathway is excessively activated in these SCC cells, while the expression of bam is attenuated. In the H1-depleted ECs, both transposon activity and DNA damage had increased dramatically, followed by EC apoptosis, which is consistent with the role of H1 in other somatic cells. Surprisingly, H1-depleted ECs acquired cap cell characteristics including dpp expression, and the resulting abnormal Dpp level inhibits SCC further differentiation. Most interestingly, double knockdown of H1 and dpp in ECs can reduce the number of SCCs to the normal level, indicating that the additional Dpp secreted by ECs contributes to the germline tumor. Taken together, our findings indicate that histone H1 is an important epigenetic factor in controlling EC characteristics and a key suppressor of germline tumor.Copyright © 2017. Published by Elsevier Inc.
Genome-wide analyses of non-syndromic cleft lip with palate identify 14 novel loci and genetic heterogeneity
Feb 24, 2017   Nature Communications
Yu Y, Zuo X, He M, Gao J, Fu Y,   . . . . . .   , Ludwig KU, Beaty TH, Zhang X, Sun L, Bian Z
Genome-wide analyses of non-syndromic cleft lip with palate identify 14 novel loci and genetic heterogeneity
Feb 24, 2017
Nature Communications
Non-syndromic cleft lip with palate (NSCLP) is the most serious sub-phenotype of non-syndromic orofacial clefts (NSOFC), which are the most common craniofacial birth defects in humans. Here we conduct a GWAS of NSCLP with multiple independent replications, totalling 7,404 NSOFC cases and 16,059 controls from several ethnicities, to identify new NSCLP risk loci, and explore the genetic heterogeneity between sub-phenotypes of NSOFC. We identify 41 SNPs within 26 loci that achieve genome-wide significance, 14 of which are novel (RAD54B, TMEM19, KRT18, WNT9B, GSC/DICER1, PTCH1, RPS26, OFCC1/TFAP2A, TAF1B, FGF10, MSX1, LINC00640, FGFR1 and SPRY1). These 26 loci collectively account for 10.94% of the heritability for NSCLP in Chinese population. We find evidence of genetic heterogeneity between the sub-phenotypes of NSOFC and among different populations. This study substantially increases the number of genetic susceptibility loci for NSCLP and provides important insights into the genetic aetiology of this common craniofacial malformation.
Untangling the genetics from the epigenetics in pancreatic cancer metastasis
Feb 24, 2017   Nature Genetics Add nature.com free-link Cancel
Vakoc CR, Tuveson DA
Untangling the genetics from the epigenetics in pancreatic cancer metastasis
Feb 24, 2017
Nature Genetics
Comparative genomic analyses of primary tumors and metastases within individuals with pancreatic cancer have exposed the complex clonal dynamics that underlie the dissemination of cancer cells to distant sites. Recent studies implicate non-genetic mechanisms in this process, particularly fluctuations in chromatin states and metabolism, which can endow rare cells within a primary tumor with metastatic potential.
Comparative Genomics Integrated with Association Analysis Identifies Candidate Effector Genes Corresponding to
Feb 24, 2017   Frontiers In Plant Science
Wu JQ, Sakthikumar S, Dong C, Zhang P, Cuomo CA, Park RF
Comparative Genomics Integrated with Association Analysis Identifies Candidate Effector Genes Corresponding to
Feb 24, 2017
Frontiers In Plant Science
Leaf rust is one of the most common and damaging diseases of wheat, and is caused by an obligate biotrophic basidiomycete,
Complex Mosaic Ring Chromosome 11 Associated with Hemizygous Loss of 8.6 Mb of 11q24.2qter in Atypical Jacobsen Syndrome
Feb 24, 2017   Molecular Syndromology
Galvão Gomes A, Paiva Grangeiro CH, Silva LR, Oliveira-Gennaro FG, Pereira CS, Joaquim TM, Panepucci RA, Squire JA, Martelli L
Complex Mosaic Ring Chromosome 11 Associated with Hemizygous Loss of 8.6 Mb of 11q24.2qter in Atypical Jacobsen Syndrome
Feb 24, 2017
Molecular Syndromology
Jacobsen syndrome (JBS) is a contiguous gene deletion syndrome involving terminal chromosome 11q. The haploinsufficiency of multiple genes contributes to the overall clinical phenotype, which can include the variant Paris-Trousseau syndrome, a transient thrombocytopenia related to
CLK-dependent exon recognition and conjoined gene formation revealed with a novel small molecule inhibitor
Feb 24, 2017   Nature Communications
Funnell T, Tasaki S, Oloumi A, Araki S, Kong E,   . . . . . .   , Morin GB, Nakanishi A, Shah S, Toyoshiba H, Aparicio S
CLK-dependent exon recognition and conjoined gene formation revealed with a novel small molecule inhibitor
Feb 24, 2017
Nature Communications
CDC-like kinase phosphorylation of serine/arginine-rich proteins is central to RNA splicing reactions. Yet, the genomic network of CDC-like kinase-dependent RNA processing events remains poorly defined. Here, we explore the connectivity of genomic CDC-like kinase splicing functions by applying graduated, short-exposure, pharmacological CDC-like kinase inhibition using a novel small molecule (T3) with very high potency, selectivity, and cell-based stability. Using RNA-Seq, we define CDC-like kinase-responsive alternative splicing events, the large majority of which monotonically increase or decrease with increasing CDC-like kinase inhibition. We show that distinct RNA-binding motifs are associated with T3 response in skipped exons. Unexpectedly, we observe dose-dependent conjoined gene transcription, which is associated with motif enrichment in the last and second exons of upstream and downstream partners, respectively. siRNA knockdown of CLK2-associated genes significantly increases conjoined gene formation. Collectively, our results reveal an unexpected role for CDC-like kinase in conjoined gene formation, via regulation of 3'-end processing and associated splicing factors.The phosphorylation of serine/arginine-rich proteins by CDC-like kinase is a central regulatory mechanism for RNA splicing reactions. Here, the authors synthesize a novel small molecule CLK inhibitor and map CLK-responsive alternative splicing events and discover an effect on conjoined gene transcription.
GIGANTEA is a co-chaperone which facilitates maturation of ZEITLUPE in the Arabidopsis circadian clock
Feb 24, 2017   Nature Communications
Cha JY, Kim J, Kim TS, Zeng Q, Wang L, Lee SY, Kim WY, Somers DE
GIGANTEA is a co-chaperone which facilitates maturation of ZEITLUPE in the Arabidopsis circadian clock
Feb 24, 2017
Nature Communications
Circadian clock systems help establish the correct daily phasing of the behavioral, developmental, and molecular events needed for the proper coordination of physiology and metabolism. The circadian oscillator comprises transcription-translation feedback loops but also requires post-translational processes that regulate clock protein homeostasis. GIGANTEA is a unique plant protein involved in the maintenance and control of numerous facets of plant physiology and development. Through an unknown mechanism GIGANTEA stabilizes the F-box protein ZEITLUPE, a key regulator of the circadian clock. Here, we show that GIGANTEA has general protein chaperone activity and can act to specifically facilitate ZEITLUPE maturation into an active form in vitro and in planta. GIGANTEA forms a ternary complex with HSP90 and ZEITLUPE and its co-chaperone action synergistically enhances HSP90/HSP70 maturation of ZEITLUPE in vitro. These results identify a molecular mechanism for GIGANTEA activity that can explain its wide-ranging role in plant biology.The plant-specific GIGANTEA protein regulates the circadian clock by stabilizing the F-box protein ZEITLUPE via an unknown mechanism. Here Cha et al. show that GIGANTEA has intrinsic chaperone activity and can facilitate ZEITLUPE maturation by acting synergistically with HSP90.
BRG1 and BRM function antagonistically with c-MYC in adult cardiomyocytes to regulate conduction and contractility
Feb 24, 2017   Journal Of Molecular And Cellular Cardiology
Willis MS, Holley DW, Wang Z, Chen X, Quintana M, Jensen BC, Tannu M, Parker J, Jeyaraj D, Jain MK, Wolfram JA, Lee HG, Bultman SJ
BRG1 and BRM function antagonistically with c-MYC in adult cardiomyocytes to regulate conduction and contractility
Feb 24, 2017
Journal Of Molecular And Cellular Cardiology
RATIONALE: The contractile dysfunction that underlies heart failure involves perturbations in multiple biological processes ranging from metabolism to electrophysiology. Yet the epigenetic mechanisms that are altered in this disease state have not been elucidated. SWI/SNF chromatin-remodeling complexes are plausible candidates based on mouse knockout studies demonstrating a combined requirement for the BRG1 and BRM catalytic subunits in adult cardiomyocytes. Brg1/Brm double mutants exhibit metabolic and mitochondrial defects and are not viable although their cause of death has not been ascertained. OBJECTIVE: To determine the cause of death of Brg1/Brm double-mutant mice, to test the hypothesis that BRG1 and BRM are required for cardiac contractility, and to identify relevant downstream target genes. METHODS AND RESULTS: A tamoxifen-inducible gene-targeting strategy utilizing αMHC-Cre-ERT was implemented to delete both SWI/SNF catalytic subunits in adult cardiomyocytes. Brg1/Brm double-mutant mice were monitored by echocardiography and electrocardiography, and they underwent rapidly progressive ventricular dysfunction including conduction defects and arrhythmias that culminated in heart failure and death within 3weeks. Mechanistically, BRG1/BRM repressed c-Myc expression, and enforced expression of a DOX-inducible c-MYC trangene in mouse cardiomyocytes phenocopied the ventricular conduction defects observed in Brg1/Brm double mutants. BRG1/BRM and c-MYC had opposite effects on the expression of cardiac conduction genes, and the directionality was consistent with their respective loss- and gain-of-function phenotypes. To support the clinical relevance of this mechanism, BRG1/BRM occupancy was diminished at the same target genes in human heart failure cases compared to controls, and this correlated with increased c-MYC expression and decreased CX43 and SCN5A expression. CONCLUSION: BRG1/BRM and c-MYC have an antagonistic relationship regulating the expression of cardiac conduction genes that maintain contractility, which is reminiscent of their antagonistic roles as a tumor suppressor and oncogene in cancer. Copyright © 2017. Published by Elsevier Ltd.

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