scholarly journals Genome-scale reconstruction of Gcn4/ATF4 networks driving a growth program

2020 ◽  
Author(s):  
Rajalakshmi Srinivasan ◽  
Adhish S. Walvekar ◽  
Aswin Seshasayee ◽  
Sunil Laxman
Keyword(s):  
Amino Acid ◽  
Ribosomal Biogenesis ◽  
Promoter Regions ◽  
Nucleotide Biosynthesis ◽  
Translation Machinery ◽  
Metabolic Genes ◽  
Genome Wide ◽  
Genome Scale ◽  
Global Growth

AbstractGrowth and starvation are considered opposite ends of a spectrum. To sustain growth, cells must manage biomolecule supply to balance constructive metabolism with high translation, through coordinated gene expression programs. Global growth programs couple increased ribosomal biogenesis with sufficient carbon metabolism, amino acid and nucleotide biosynthesis, and how this is collectively managed is a fundamental question. Conventionally, the role of the Gcn4/ATF4 transcription factor has been studied only in the context of amino acid starvation. However, high Gcn4/ATF4 has been observed in contexts of rapid cell proliferation, and the specific role of Gcn4 in growth contexts are unclear. Here, using a methionine-induced growth program in yeast, we show that Gcn4/ATF4 is the fulcrum through which metabolic supply dependent sustenance of translation outputs is maintained. Integrating time-matched transcriptome and ChIP-Seq analysis, we decipher genome-wide direct and indirect roles for Gcn4 in this growth program. Genes that enable metabolic precursor biosynthesis indispensably require Gcn4; contrastingly ribosomal genes are partly repressed by Gcn4. Gcn4 directly binds promoter-regions and transcribes a subset of metabolic genes, particularly driving lysine and arginine biosynthesis. Gcn4 also globally represses lys/arg enriched transcripts, which include the translation machinery. The sustained Gcn4 dependent lys/arg supply is required to maintain sufficient translation capacity, by allowing the synthesis of the translation machinery itself. Gcn4 thereby enables metabolic-precursor supply to bolster protein synthesis, and drive a growth program. Thus, we illustrate how growth and starvation outcomes are both controled using the same Gcn4 transcriptional outputs, in entirely distinct contexts.

scholarly journals Genome-scale reconstruction of Gcn4/ATF4 networks driving a growth program

PLoS Genetics ◽  
2020 ◽  
Vol 16 (12) ◽  
pp. e1009252
Author(s):  
Rajalakshmi Srinivasan ◽  
Adhish S. Walvekar ◽  
Zeenat Rashida ◽  
Aswin Seshasayee ◽  
Sunil Laxman
Keyword(s):  
Amino Acid ◽  
Promoter Regions ◽  
Nucleotide Biosynthesis ◽  
Translation Machinery ◽  
Metabolic Genes ◽  
Genome Wide ◽  
Genes Encoding ◽  
Genome Scale ◽  
Global Growth

Growth and starvation are considered opposite ends of a spectrum. To sustain growth, cells use coordinated gene expression programs and manage biomolecule supply in order to match the demands of metabolism and translation. Global growth programs complement increased ribosomal biogenesis with sufficient carbon metabolism, amino acid and nucleotide biosynthesis. How these resources are collectively managed is a fundamental question. The role of the Gcn4/ATF4 transcription factor has been best studied in contexts where cells encounter amino acid starvation. However, high Gcn4 activity has been observed in contexts of rapid cell proliferation, and the roles of Gcn4 in such growth contexts are unclear. Here, using a methionine-induced growth program in yeast, we show that Gcn4/ATF4 is the fulcrum that maintains metabolic supply in order to sustain translation outputs. By integrating matched transcriptome and ChIP-Seq analysis, we decipher genome-wide direct and indirect roles for Gcn4 in this growth program. Genes that enable metabolic precursor biosynthesis indispensably require Gcn4; contrastingly ribosomal genes are partly repressed by Gcn4. Gcn4 directly binds promoter-regions and transcribes a subset of metabolic genes, particularly driving lysine and arginine biosynthesis. Gcn4 also globally represses lysine and arginine enriched transcripts, which include genes encoding the translation machinery. The Gcn4 dependent lysine and arginine supply thereby maintains the synthesis of the translation machinery. This is required to maintain translation capacity. Gcn4 consequently enables metabolic-precursor supply to bolster protein synthesis, and drive a growth program. Thus, we illustrate how growth and starvation outcomes are both controlled using the same Gcn4 transcriptional outputs that function in distinct contexts.

scholarly journals Genome-Wide Identification of WRKY Genes in Artemisia annua: Characterization of a Putative Ortholog of AtWRKY40

Plants ◽  
2020 ◽  
Vol 9 (12) ◽  
pp. 1669
Author(s):  
Angelo De Paolis ◽  
Sofia Caretto ◽  
Angela Quarta ◽  
Gian-Pietro Di Sansebastiano ◽  
Irene Sbrocca ◽  
...  
Keyword(s):  
Artemisia Annua ◽  
Antimalarial Activity ◽  
Regulatory Elements ◽  
Promoter Regions ◽  
Cis Acting ◽  
Protein Motifs ◽  
Genome Wide ◽  
A Genome ◽  
Rapid Amplification

Artemisia annua L. is well-known as the plant source of artemisinin, a sesquiterpene lactone with effective antimalarial activity. Here, a putative ortholog of the Arabidopsis thaliana WRKY40 transcription factor (TF) was isolated via reverse transcription-polymerase chain reaction and rapid amplification of cDNA ends in A. annua and named AaWRKY40. A putative nuclear localization domain was identified in silico and experimentally confirmed by using protoplasts of A. annua transiently transformed with AaWRKY40-GFP. A genome-wide analysis identified 122 WRKY genes in A. annua, and a manually curated database was obtained. The deduced proteins were categorized into the major WRKY groups, with group IIa containing eight WRKY members including AaWRKY40. Protein motifs, gene structure, and promoter regions of group IIa WRKY TFs of A. annua were characterized. The promoter region of AaWRKY group IIa genes contained several abiotic stress cis-acting regulatory elements, among which a highly conserved W-box motif was identified. Expression analysis of AaWRKY40 compared to AaWRKY1 in A. annua cell cultures treated with methyl jasmonate known to enhance artemisinin production, suggested a possible involvement of AaWRKY40 in terpenoid metabolism. Further investigation is necessary to study the role of AaWRKY40 and possible interactions with other TFs in A. annua.

scholarly journals Metabolic Responses of Carotenoid and Cordycepin Biosynthetic Pathways in Cordyceps militaris under Light-Programming Exposure through Genome-Wide Transcriptional Analysis

Biology ◽  
2020 ◽  
Vol 9 (9) ◽  
pp. 242
Author(s):  
Roypim Thananusak ◽  
Kobkul Laoteng ◽  
Nachon Raethong ◽  
Yu Zhang ◽  
Wanwipa Vongsangnak
Keyword(s):  
Process Development ◽  
Light Exposure ◽  
Carotenoid Biosynthesis ◽  
Cordyceps Militaris ◽  
Transcriptional Analysis ◽  
Metabolic Responses ◽  
Abiotic Factor ◽  
Metabolic Genes ◽  
Genome Wide ◽  
Genome Scale

Cordyceps militaris is currently exploited for commercial production of specialty products as its biomass constituents are enriched in bioactive compounds, such as cordycepin. The rational process development is important for economically feasible production of high quality bioproducts. Light is an abiotic factor affecting the cultivation process of this entomopathogenic fungus, particularly in its carotenoid formation. To uncover the cell response to light exposure, this study aimed to systematically investigate the metabolic responses of C. militaris strain TBRC6039 using integrative genome-wide transcriptome and genome-scale metabolic network (GSMN)-driven analysis. The genome-wide transcriptome analysis showed 8747 expressed genes in the glucose and sucrose cultures grown under light-programming and dark conditions. Of them, 689 differentially expressed genes were significant in response to the light-programming exposure. Through integration with the GSMN-driven analysis using the improved network (iRT1467), the reporter metabolites, e.g., adenosine-5′-monophosphate (AMP) and 2-oxoglutarate, were identified when cultivated under the carotenoid-producing condition controlled by light-programming exposure, linking to up-regulations of the metabolic genes involved in glyoxalase system, as well as cordycepin and carotenoid biosynthesis. These results indicated that C. militaris had a metabolic control in acclimatization to light exposure through transcriptional co-regulation, which supported the cell growth and cordycepin production in addition to the accumulation of carotenoid as a photo-protective bio-pigment. This study provides a perspective in manipulating the metabolic fluxes towards the target metabolites through either genetic or physiological approaches.

scholarly journals Interferon lambda 4 impacts broadly on hepatitis C virus diversity

2018 ◽  
Author(s):  
M Azim Ansari ◽  
Elihu Aranday-Cortes ◽  
Camilla LC Ip ◽  
Ana da Silva Filipe ◽  
Lau Siu Hin ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Viral Load ◽  
Hepatitis C ◽  
Amino Acid ◽  
Active Form ◽  
Hcv Infection ◽  
Virus Diversity ◽  
Genome Wide ◽  
Amino Acid Diversity

AbstractType III interferons (IFN-λ) are part of the innate immune response to hepatitis C virus (HCV) infection however the specific role of IFN-λ4 and the nature of the viral adaption to this pressure have not been defined. Here we use paired genome-wide human and viral genetic data in 485 patients infected with HCV genotype 3a to explore the role of IFN-λ4 on HCV evolution during chronic infection. We show that genetic variations within the host IFNL4 locus have a broad and systematic impact on HCV amino acid diversity. We also demonstrate that this impact is larger in patients producing a more active form of IFN-λ4 protein compared to the less active form. A similar observation was noted for viral load. We conclude that IFN-λ4 protein is a likely causal agent driving widespread HCV amino acid changes and associated with viral load and possibly other clinical and biological outcomes of HCV infection.

Amino acid permease 6 modulates host response to cyst nematodes in wheat and Arabidopsis

Nematology ◽  
2018 ◽  
Vol 20 (8) ◽  
pp. 737-750 ◽  
Author(s):  
Shree R. Pariyar ◽  
Jenish Nakarmi ◽  
Muhammad Arslan Anwer ◽  
Shahid Siddique ◽  
Muhammad Ilyas ◽  
...  
Keyword(s):  
Amino Acid ◽  
Genome Wide Association Study ◽  
Cyst Nematode ◽  
Female Size ◽  
Cyst Nematodes ◽  
Amino Acid Permease ◽  
Knock Out ◽  
Genome Wide ◽  
Nematode Parasitism

Summary Cyst nematodes are plant parasites that cause significant crop loss in wheat and other crops. Infective juveniles invade roots and induce syncytial feeding structures as the only source of nutrients throughout their life. A previous genome-wide association study in wheat identified amino acid permease 6 (TaAAP6) to be linked to susceptibility to the cereal cyst nematode Heterodera filipjevi. To characterise the role of AAP6 during nematode parasitism, we analysed the expression of TaAAP6 and the Arabidopsis orthologue AtAAP6. TaAAP6 was found to be highly expressed in nematode-infected roots of susceptible wheat, whereas it was not upregulated in nematode-infected roots of resistant accessions. AtAAP6 was also found to be highly upregulated in nematode-induced syncytia compared with non-infected roots. Infection assays with an AtAAP6 knock-out mutant revealed reduction in developing females, female size, and size of female-associated syncytia, thus indicating the importance of AAP6 in cyst nematode parasitism.

O-118 New insight into the genetic contribution of common variants to the development of extreme phenotypes of unexplained male infertility: a multicenter genome-wide association study

2021 ◽  
Vol 36 (Supplement_1) ◽  
Author(s):  
M Cerván Martín ◽  
F Tüttelmann ◽  
A M Lopes ◽  
L Bossini-Castillo ◽  
N Garrido ◽  
...  
Keyword(s):  
Genetic Variation ◽  
Amino Acid ◽  
Male Infertility ◽  
Mhc Class Ii ◽  
Genome Wide Association Study ◽  
Genome Wide Association ◽  
Common Genetic Variation ◽  
Genome Wide ◽  
Mhc Alleles

Abstract Study question What is the contribution of the common genetic variation to the development of unexplained male infertility due to severe spermatogenic failure (SPGF)? Summary answer Genetic polymorphisms of key immune and spermatogenesis loci are involved in the etiology of the most severe SPGF cases, defined by Sertoli cell-only (SCO) phenotype. What is known already Male infertility is a rising worldwide concern that affects millions of couples. Non-obstructive azoospermia (NOA) and severe oligospermia (SO) are two extreme manifestations characterized by SPGF. A genetic cause can be established in only around 20% of affected men, with the remaining cases being classified as otherwise unexplained. To date, the genome-wide association study (GWAS) strategy, although already successfully applied in several other complex traits and diseases, was less fruitful in studies that attempted to decipher the genetic component of unexplained SPGF, mainly due to both a lack of well-powered samples in different ancestries and limitations in study design. Study design, size, duration We designed a GWAS for unexplained male infertility due to SPGF including a total of 1,274 affected cases and 1,951 fertile controls from the Iberian Peninsula (Spain and Portugal) and Germany. Different biostatistics and bioinformatics approaches were used to evaluate the possible effect of single-nucleotide polymorphisms (SNPs) across the whole genome in the susceptibility to specific subtypes of unexplained SPGF. Participants/materials, setting, methods The case cohort comprised 502 SO and 772 NOA patients, who were subdivided according to histological phenotypes (SCO, maturation arrest, and hypospermatogenesis) and the outcome of testicular sperm extraction techniques (TESE) from testis biopsies. Genotyping was performed with the GSA platform (Illumina). After quality-control and genotype imputation, 6,539,982 SNPs remained for the analysis, which was performed by logistic regression models. The datasets went through a meta-analysis by the inverse variance weighted method under fixed effects. Main results and the role of chance Genetic associations with SCO at the genome-wide-level of significance were identified in the major histocompatibility (MHC) class II region (rs1136759, OR = 1.80, P = 1.32E-08) and in a regulatory region of chromosome 14 nearby the vaccinia-related kinase 1 (VRK1) gene (rs115054029, OR = 3.14, P = 4.37-08). VRK1 is a relevant proliferative factor for spermatogenesis that causes progressive loss of spermatogonia when disrupted in mouse models. The role of the MHC system in SCO susceptibility was comprehensively evaluated through a validated imputation method that infers classical MHC alleles and polymorphic amino acid positions. A serine at position 13 of the HLA-DRβ1 protein (defined by the risk allele of the lead variant rs1136759) explained most of the SCO association signals within the MHC class II region. This residue is located in the binding pocket of the HLA-DR molecule and interacts directly with the presented antigen. Interestingly, position 13 of HLA-DRβ1 is the most relevant risk amino acid position for a wide spectrum of immune-mediated disorders. The HLA-DRB1*13 haplotype (which includes the serine at position 13 and represents the strongest NOA-associated marker in Asians to date) was the strongest signal amongst the classical MHC alleles in our study cohort (OR = 1.93, P = 9.90E-07). Limitations, reasons for caution Although the statistical power for the overall analysis was appropriate, the subphenotype analyses performed had considerably lower counts, which may influence the identification of genetic variants conferring low to moderate risk effects. Independent studies in larger SCO study cohorts should be performed to confirm our findings. Wider implications of the findings The molecular mechanisms underlying unexplained SPGF are largely unknown. Our data suggest a relevant role of common genetic variation in the development of SCO, the most extreme histological phenotype of NOA. SCO is characterized by the loss of germ cells and, therefore, implies a considerably higher probability of unsuccessful TESE. Trial registration number N/A

scholarly journals Genome-wide identification of the PEBP genes in pears and the putative role of PbFT in flower bud differentiation

PeerJ ◽  
2020 ◽  
Vol 8 ◽  
pp. e8928
Author(s):  
Shuliang Zhao ◽  
Yarui Wei ◽  
Hongguang Pang ◽  
Jianfeng Xu ◽  
Yingli Li ◽  
...  
Keyword(s):  
Expression Patterns ◽  
Day Length ◽  
Promoter Regions ◽  
Flower Bud ◽  
Genome Wide ◽  
Flower Bud Differentiation ◽  
Vegetative And Reproductive Growth ◽  
And Function ◽  
Phosphatidylethanolamine Binding Protein

Although Phosphatidylethanolamine-binding protein (PEBP) genes have been identified in several plants, little is known about PEBP genes in pears. In this study, a total of 24 PEBP genes were identified, in which 10, 5 and 9 were from Pyrus bretschneideri genome, Pyrus communis genome and Pyrus betuleafolia genome, respectively. Subsequently, gene structure, phylogenetic relationship, chromosomal localization, promoter regions, collinearity and expression were determined with these PEBP genes. It was found that only PbFT from PEBP genes of P. bretschneideri was relatively highly expressed in leaves during flower bud differentiation. Whereas, expression patterns of TFL1 homologues, gene23124 and gene16540, were different from PbFT in buds. The expression pattern and the treatment of reduction day-length indicated that the expression of PbFT in leaves were regulated by day-length and circadian clock. Additionally, the phenotype of transgenic Arabidopsis suggested that PbFT played a role in not only promoting flower bud differentiation, but also regulating the balance between vegetative and reproductive growth. These results may provide important information for further understanding of the evolution and function of PEBP genes in pears.

An ESR study of the peroxidase reaction catalyzed by human methaemoglobin and methaemoglobin-haptoglobin complex

1991 ◽  
Vol 56 (4) ◽  
pp. 923-932
Author(s):  
Jana Stejskalová ◽  
Pavel Stopka ◽  
Zdeněk Pavlíček
Keyword(s):  
Hydrogen Peroxide ◽  
Ascorbic Acid ◽  
Amino Acid ◽  
Peroxidase Activity ◽  
Amino Acid Analysis ◽  
Superoxide Radical ◽  
Esr Spectra ◽  
The Other ◽  
Delocalized Electron

The ESR spectra of peroxidase systems of methaemoglobin-ascorbic acid-hydrogen peroxide and methaemoglobin-haptoglobin complex-ascorbic acid-hydrogen peroxide have been measured in the acetate buffer of pH 4.5. For the system with methaemoglobin an asymmetrical signal with g ~ 2 has been observed which is interpreted as the perpendicular region of anisotropic spectrum of superoxide radical. On the other hand, for the system with methaemoglobin-haptoglobin complex the observed signal with g ~ 2 is symmetrical and is interpreted as a signal of delocalized electron. After realization of three repeatedly induced peroxidase processes the ESR signal of the perpendicular part of anisotropic spectrum of superoxide radical is distinctly diminished, whereas the signal of delocalized electron remains practically unchanged. An amino acid analysis of methaemoglobin along with results of the ESR measurements make it possible to derive a hypothesis about the role of haptoglobin in increasing of the peroxidase activity of methaemoglobin.

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