Genes

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Open AccessReview

Disruption of the Gut Microbiome: Clostridium difficile Infection and the Threat of Antibiotic Resistance

by Priscilla A. Johanesen, Kate E. Mackin, Melanie L. Hutton, Milena M. Awad, Sarah Larcombe, Jacob M. Amy and Dena Lyras

Genes 2015, 6(4), 1347-1360; https://doi.org/10.3390/genes6041347 - 21 Dec 2015

Cited by 81 | Viewed by 10883

Abstract

Clostridium difficile is well recognized as the leading cause of antibiotic-associated diarrhea, having a significant impact in both health-care and community settings. Central to predisposition to C. difficile infection is disruption of the gut microbiome by antibiotics. Being a Gram-positive anaerobe, C. difficile [...] Read more.

Clostridium difficile is well recognized as the leading cause of antibiotic-associated diarrhea, having a significant impact in both health-care and community settings. Central to predisposition to C. difficile infection is disruption of the gut microbiome by antibiotics. Being a Gram-positive anaerobe, C. difficile is intrinsically resistant to a number of antibiotics. Mobile elements encoding antibiotic resistance determinants have also been characterized in this pathogen. While resistance to antibiotics currently used to treat C. difficile infection has not yet been detected, it may be only a matter of time before this occurs, as has been seen with other bacterial pathogens. This review will discuss C. difficile disease pathogenesis, the impact of antibiotic use on inducing disease susceptibility, and the role of antibiotic resistance and mobile elements in C. difficile epidemiology. Full article

(This article belongs to the Special Issue Antibiotic Resistance: Mobility and Microbiomes)

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Open AccessArticle

Transcriptomic Analysis of the Porcine Endometrium during Embryo Implantation

by Haichao Lin, Huaizhong Wang, Yanping Wang, Chang Liu, Cheng Wang and Jianfeng Guo

Genes 2015, 6(4), 1330-1346; https://doi.org/10.3390/genes6041330 - 21 Dec 2015

Cited by 33 | Viewed by 5883

Abstract

In pigs, successful embryo implantation is an important guarantee for producing litter size, and early embryonic loss occurring on day 12–30 of gestation critically affects the potential litter size. The implantation process is regulated by the expression of numerous genes, so comprehensive analysis [...] Read more.

In pigs, successful embryo implantation is an important guarantee for producing litter size, and early embryonic loss occurring on day 12–30 of gestation critically affects the potential litter size. The implantation process is regulated by the expression of numerous genes, so comprehensive analysis of the endometrium is necessary. In this study, RNA sequencing (RNA-Seq) technology is used to analyze endometrial tissues during early pregnancy. We investigated the changes of gene expression between three stages (day 12, 18, and 25) by multiple comparisons. There were 1557, 8951, and 2345 differentially expressed genes (DEGs) revealed between the different periods of implantation. We selected several genes for validation by the use of quantitative real-time RT-PCR. Bioinformatic analysis of differentially expressed genes in the endometrium revealed a number of biological processes and pathways potentially involved in embryo implantation in the pig, most noticeably cell proliferation, regulation of immune response, interaction of cytokine-cytokine receptors, and cell adhesion. These results showed that specific gene expression patterns reflect the different functions of the endometrium in three stages (maternal recognition, conceptus attachment, and embryo implantation). This study identified comprehensive transcriptomic profile in the porcine endometrium and thus could be a foundation for targeted studies of genes and pathways potentially involved in abnormal endometrial receptivity and embryo loss in early pregnancy. Full article

(This article belongs to the Section Population and Evolutionary Genetics and Genomics)

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Open AccessArticle

Molecular Modeling of Myrosinase from Brassica oleracea: A Structural Investigation of Sinigrin Interaction

by Sathishkumar Natarajan, Senthil Kumar Thamilarasan, Jong-In Park, Mi-Young Chung and Ill-Sup Nou

Genes 2015, 6(4), 1315-1329; https://doi.org/10.3390/genes6041315 - 21 Dec 2015

Cited by 11 | Viewed by 6292

Abstract

Myrosinase, which is present in cruciferous plant species, plays an important role in the hydrolysis of glycosides such as glucosinolates and is involved in plant defense. Brassicaceae myrosinases are diverse although they share common ancestry, and structural knowledge about myrosinases from cabbage ( [...] Read more.

Myrosinase, which is present in cruciferous plant species, plays an important role in the hydrolysis of glycosides such as glucosinolates and is involved in plant defense. Brassicaceae myrosinases are diverse although they share common ancestry, and structural knowledge about myrosinases from cabbage (Brassica oleracea) was needed. To address this, we constructed a three-dimensional model structure of myrosinase based on Sinapis alba structures using Iterative Threading ASSEmbly Refinement server (I-TASSER) webserver, and refined model coordinates were evaluated with ProQ and Verify3D. The resulting model was predicted with β/α fold, ten conserved N-glycosylation sites, and three disulfide bridges. In addition, this model shared features with the known Sinapis alba myrosinase structure. To obtain a better understanding of myrosinase–sinigrin interaction, the refined model was docked using Autodock Vina with crucial key amino acids. The key nucleophile residues GLN207 and GLU427 were found to interact with sinigrin to form a hydrogen bond. Further, 20-ns molecular dynamics simulation was performed to examine myrosinase–sinigrin complex stability, revealing that residue GLU207 maintained its hydrogen bond stability throughout the entire simulation and structural orientation was similar to that of the docked state. This conceptual model should be useful for understanding the structural features of myrosinase and their binding orientation with sinigrin. Full article

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Open AccessArticle

Exploring Folate Diversity in Wild and Primitive Potatoes for Modern Crop Improvement

by Bruce R. Robinson, Vidyasagar Sathuvalli, John Bamberg and Aymeric Goyer

Genes 2015, 6(4), 1300-1314; https://doi.org/10.3390/genes6041300 - 8 Dec 2015

Cited by 21 | Viewed by 5361

Abstract

Malnutrition is one of the world’s largest health concerns. Folate (also known as vitamin B₉) is essential in the human diet, and without adequate folate intake, several serious health concerns, such as congenital birth defects and an increased risk of stroke [...] Read more.

Malnutrition is one of the world’s largest health concerns. Folate (also known as vitamin B₉) is essential in the human diet, and without adequate folate intake, several serious health concerns, such as congenital birth defects and an increased risk of stroke and heart disease, can occur. Most people’s folate intake remains sub-optimal, even in countries that have a folic acid food fortification program in place. Staple crops, such as potatoes, represent an appropriate organism for biofortification through traditional breeding based on their worldwide consumption and the fact that modern cultivars only contain about 6% of the daily recommended intake of folate. To start breeding potatoes with enhanced folate content, high folate potato material must be identified. In this study, 250 individual plants from 77 accessions and 10 Solanum species were screened for their folate content using a tri-enzyme extraction and microbial assay. There was a 10-fold range of folate concentrations among individuals. Certain individuals within the species Solanum tuberosum subsp. andigenum, Solanum vernei and Solanum boliviense have the potential to produce more than double the folate concentrations of commercial cultivars, such as Russet Burbank. Our results show that tapping into the genetic diversity of potato is a promising approach to increase the folate content of this important crop. Full article

(This article belongs to the Special Issue Genetic Diversity for Crop Improvement)

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Open AccessArticle

A Meta-Analysis of the Association between Polymorphisms in MicroRNAs and Risk of Ischemic Stroke

by Yan Xiao, Mei-Hua Bao, Huai-Qing Luo, Ju Xiang and Jian-Ming Li

Genes 2015, 6(4), 1283-1299; https://doi.org/10.3390/genes6041283 - 7 Dec 2015

Cited by 13 | Viewed by 4286

Abstract

Ischemic stroke (IS) is responsible for a high death rate and for adult disability worldwide. MiR-146a (rs2910164), miR-149 (rs2292832), miR-196a2 (rs11614913) and miR-499 (rs3746444) are found to be associated with ischemic stroke. However, the results were inconsistent and inconclusive. The present study performed [...] Read more.

Ischemic stroke (IS) is responsible for a high death rate and for adult disability worldwide. MiR-146a (rs2910164), miR-149 (rs2292832), miR-196a2 (rs11614913) and miR-499 (rs3746444) are found to be associated with ischemic stroke. However, the results were inconsistent and inconclusive. The present study performed a meta-analysis to get a more precise and comprehensive estimation of the association between the four polymorphisms and IS risk. The databases Pubmed, Embase, Cochrane Central Register of Controlled Trials, Chinese National Knowledge Infrastructure, and Chinese Biomedical Literature Database were searched for related studies. A total of five studies including 2230 cases and 2229 controls were identified for the meta-analysis. The results indicate that TT genotype and T allele of miR-149 (rs2292832) are associated with significantly lower risks of IS in a homozygous model (OR = 0.70) and an allelic model (OR = 0.86). No significant associations were found between miR-146a (rs2910164), miR-196a2 (rs11614913), miR-499 (3746444) and IS susceptibility in any of the studies. However, subgroup analysis by sample size indicates a significant decrease in risks of IS for CC genotype and C allele of miR-146a (rs2910164) in the large sample size group. Therefore, miR-149 (rs2292832) might be recommended as a predictor for IS risk, while miR-146a (rs2910164), miR-196a2 (rs11614913), miR-499 (3746444) are not. Full article

(This article belongs to the Section Human Genomics and Genetic Diseases)

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Open AccessArticle

Characterization of Thermotolerant Chitinases Encoded by a Brevibacillus laterosporus Strain Isolated from a Suburban Wetland

by Pulin Liu, Deyong Cheng and Lihong Miao

Genes 2015, 6(4), 1268-1282; https://doi.org/10.3390/genes6041268 - 4 Dec 2015

Cited by 13 | Viewed by 4380

Abstract

To isolate and characterize chitinases that can be applied with practical advantages, 57 isolates of chitin-degrading bacteria were isolated from the soil of a suburban wetland. 16S rRNA gene analysis revealed that the majority of these strains belonged to two genera, Paenibacillus and [...] Read more.

To isolate and characterize chitinases that can be applied with practical advantages, 57 isolates of chitin-degrading bacteria were isolated from the soil of a suburban wetland. 16S rRNA gene analysis revealed that the majority of these strains belonged to two genera, Paenibacillus and Brevibacillus. Taking thermostability into account, the chitinases (ChiA and ChiC) of a B. laterosporus strain were studied further. Ni-NTA affinity-purified ChiA and ChiC were optimally active at pH 7.0 and 6.0, respectively, and showed high temperature stability up to 55 °C. Kinetic analysis revealed that ChiC has a lower affinity and stronger catalytic activity toward colloidal chitin than ChiA. With their stability in a broad temperature range, ChiA and ChiC can be utilized for the industrial bioconversion of chitin wastes into biologically active products. Full article

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Open AccessArticle

Daptomycin-Nonsusceptible Staphylococcus aureus: The Role of Combination Therapy with Daptomycin and Gentamicin

by Jhih-Hang Jiang and Anton Y. Peleg

Genes 2015, 6(4), 1256-1267; https://doi.org/10.3390/genes6041256 - 30 Nov 2015

Cited by 12 | Viewed by 5720

Abstract

Reduced susceptibility to daptomycin in Staphylococcus aureus has now been described, leading to clinical failures. Here we determined the impact of daptomycin and gentamicin combination therapy on bactericidal activity and resistance emergence using daptomycin-susceptible and -resistant isolates with mutations linked to previous daptomycin [...] Read more.

Reduced susceptibility to daptomycin in Staphylococcus aureus has now been described, leading to clinical failures. Here we determined the impact of daptomycin and gentamicin combination therapy on bactericidal activity and resistance emergence using daptomycin-susceptible and -resistant isolates with mutations linked to previous daptomycin or vancomycin exposure. Enhanced killing of S. aureus was observed when gentamicin was combined with daptomycin, most commonly with daptomycin concentrations below the peak serum free-drug concentrations achieved with standard dosing. Synergy was seen with daptomycin-susceptible isolates and with isolates resistant to vancomycin and daptomycin. Combination therapy also prevented the emergence of resistance. Daptomycin and gentamicin combination therapy may provide the synergy required to prevent emergence of resistance when daptomycin levels are below peak serum concentrations as would be found in deep-seated, complicated infections. Full article

(This article belongs to the Special Issue Antibiotic Resistance: Mobility and Microbiomes)

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Open AccessArticle

Molecular and Cytogenetic Characterization of New Wheat—Dasypyrum breviaristatum Derivatives with Post-Harvest Re-Growth Habit

by Hongjun Zhang, Guangrong Li, Donghai Li, Dan Gao, Jie Zhang, Ennian Yang and Zujun Yang

Genes 2015, 6(4), 1242-1255; https://doi.org/10.3390/genes6041242 - 27 Nov 2015

Cited by 9 | Viewed by 5722

Abstract

A novel Dasypyrum species, Dasypyrum breviaristatum, serves as a valuable source of useful genes for wheat improvement. The development and characterization of new wheat—D. breviaristatum introgression lines is important to determine the novel gene(s) on specific chromosome(s). We first used multi-color [...] Read more.

A novel Dasypyrum species, Dasypyrum breviaristatum, serves as a valuable source of useful genes for wheat improvement. The development and characterization of new wheat—D. breviaristatum introgression lines is important to determine the novel gene(s) on specific chromosome(s). We first used multi-color fluorescence in situ hybridization (FISH) to identify the individual D. breviaristatum V^b chromosomes in a common wheat—D. breviaristatum partial amphiploid, TDH-2. The FISH patterns of D. breviaristatum chromosomes were different from those of D. villosum chromosomes. Lines D2146 and D2150 were selected from a cross between wheat line MY11 and wheat—D. breviaristatum partial amphiploid TDH-2, and they were characterized by FISH and PCR-based molecular markers. We found that D2150 was a monosomic addition line for chromosome 5V^b of D. breviaristatum, while D2146 had the 5V^bL chromosome arm translocated with wheat chromosome 5AS. Molecular marker analysis confirmed that the introduced D. breviaristatum chromosome 5V^bL translocation possessed a duplicated region homoeologous to 5AS, revealing that the 5AS.5V^bL translocation may not functionally compensate well. The dwarfing and the pre-harvest re-growth habits observed in the wheat—D. breviaristatum chromosome 5V^b derivatives may be useful for future development of perennial growth wheat lines. Full article

(This article belongs to the Special Issue Genetic Diversity for Crop Improvement)

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Open AccessArticle

Haplotypes and Sequence Variation in the Ovine Adiponectin Gene (ADIPOQ)

by Qing-Ming An, Hui-Tong Zhou, Jiang Hu, Yu-Zhu Luo and Jon G. H. Hickford

Genes 2015, 6(4), 1230-1241; https://doi.org/10.3390/genes6041230 - 23 Nov 2015

Cited by 4 | Viewed by 4184

Abstract

The adiponectin gene (ADIPOQ) plays an important role in energy homeostasis. In this study five separate regions (regions 1 to 5) of ovine ADIPOQ were analysed using PCR-SSCP. Four different PCR-SSCP patterns (A₁-D₁, A₂-D [...] Read more.

The adiponectin gene (ADIPOQ) plays an important role in energy homeostasis. In this study five separate regions (regions 1 to 5) of ovine ADIPOQ were analysed using PCR-SSCP. Four different PCR-SSCP patterns (A₁-D₁, A₂-D₂) were detected in region-1 and region-2, respectively, with seven and six SNPs being revealed. In region-3, three different patterns (A₃-C₃) and three SNPs were observed. Two patterns (A₄-B₄, A₅-B₅) and two and one SNPs were observed in region-4 and region-5, respectively. In total, nineteen SNPs were detected, with five of them in the coding region and two (c.46T/C and c.515G/A) putatively resulting in amino acid changes (p.Tyr16His and p.Lys172Arg). In region-1, -2 and -3 of 316 sheep from eight New Zealand breeds, variants A₁, A₂ and A₃ were the most common, although variant frequencies differed in the eight breeds. Across region-1 and region-3, nine haplotypes were identified and haplotypes A₁-A₃, A₁-C₃, B₁-A₃ and B₁-C₃ were most common. These results indicate that the ADIPOQ gene is polymorphic and suggest that further analysis is required to see if the variation in the gene is associated with animal production traits. Full article

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Open AccessArticle

Identification of Candidate Genes for Seed Glucosinolate Content Using Association Mapping in Brassica napus L.

by Cun-Min Qu, Shi-Meng Li, Xiu-Jian Duan, Jin-Hua Fan, Le-Dong Jia, Hui-Yan Zhao, Kun Lu, Jia-Na Li, Xin-Fu Xu and Rui Wang

Genes 2015, 6(4), 1215-1229; https://doi.org/10.3390/genes6041215 - 18 Nov 2015

Cited by 44 | Viewed by 7430

Abstract

Rapeseed contains glucosinolates, a toxic group of sulfur-containing glucosides, which play critical roles in defense against herbivores and microbes. However, the presence of glucosinolates in rapeseed reduces the value of the meal as feed for livestock. We performed association mapping of seed glucosinolate [...] Read more.

Rapeseed contains glucosinolates, a toxic group of sulfur-containing glucosides, which play critical roles in defense against herbivores and microbes. However, the presence of glucosinolates in rapeseed reduces the value of the meal as feed for livestock. We performed association mapping of seed glucosinolate (GS) content using the 60K Brassica Infinium single nucleotide polymorphism (SNP) array in 520 oilseed rape accessions. A total of 11 peak SNPs significantly associated with GS content were detected in growing seasons of 2013 and 2014 and were located on B. napus chromosomes A08, A09, C03, and C09, respectively. Two associated regions of GS content covered by these markers were further verified, and three B. napus homologous genes involved in the biosynthesis and accumulation of GS were identified. These genes were multigene family members and were distributed on different chromosomes. Moreover, two genes (BnGRT2 and BnMYB28) associated with GS content were validated by the qRT-PCR analysis of their expression profiles. The further identification and functionalization of these genes will provide useful insight into the mechanism underlying GS biosynthesis and allocation in B. napus, and the associated SNPs markers could be helpful for molecular maker-assisted breeding for low seed GS in B. napus. Full article

(This article belongs to the Special Issue Genetic Diversity for Crop Improvement)

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Open AccessArticle

Identification of Differentially Expressed IGFBP5-Related Genes in Breast Cancer Tumor Tissues Using cDNA Microarray Experiments

by Mustafa Akkiprik, İrem Peker, Tolga Özmen, Gökçe Güllü Amuran, Bahadır M. Güllüoğlu, Handan Kaya and Ayşe Özer

Genes 2015, 6(4), 1201-1214; https://doi.org/10.3390/genes6041201 - 10 Nov 2015

Cited by 23 | Viewed by 6835

Abstract

IGFBP5 is an important regulatory protein in breast cancer progression. We tried to identify differentially expressed genes (DEGs) between breast tumor tissues with IGFBP5 overexpression and their adjacent normal tissues. In this study, thirty-eight breast cancer and adjacent normal breast tissue samples were [...] Read more.

IGFBP5 is an important regulatory protein in breast cancer progression. We tried to identify differentially expressed genes (DEGs) between breast tumor tissues with IGFBP5 overexpression and their adjacent normal tissues. In this study, thirty-eight breast cancer and adjacent normal breast tissue samples were used to determine IGFBP5 expression by qPCR. cDNA microarrays were applied to the highest IGFBP5 overexpressed tumor samples compared to their adjacent normal breast tissue. Microarray analysis revealed that a total of 186 genes were differentially expressed in breast cancer compared with normal breast tissues. Of the 186 genes, 169 genes were downregulated and 17 genes were upregulated in the tumor samples. KEGG pathway analyses showed that protein digestion and absorption, focal adhesion, salivary secretion, drug metabolism-cytochrome P450, and phenylalanine metabolism pathways are involved. Among these DEGs, the prominent top two genes (MMP11 and COL1A1) which potentially correlated with IGFBP5 were selected for validation using real time RT-qPCR. Only COL1A1 expression showed a consistent upregulation with IGFBP5 expression and COL1A1 and MMP11 were significantly positively correlated. We concluded that the discovery of coordinately expressed genes related with IGFBP5 might contribute to understanding of the molecular mechanism of the function of IGFBP5 in breast cancer. Further functional studies on DEGs and association with IGFBP5 may identify novel biomarkers for clinical applications in breast cancer. Full article

(This article belongs to the Section Human Genomics and Genetic Diseases)

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Open AccessReview

Super Enhancers in Cancers, Complex Disease, and Developmental Disorders

by Adrienne R. Niederriter, Arushi Varshney, Stephen C. J. Parker and Donna M. Martin

Genes 2015, 6(4), 1183-1200; https://doi.org/10.3390/genes6041183 - 9 Nov 2015

Cited by 62 | Viewed by 12934

Abstract

Recently, unique areas of transcriptional regulation termed super-enhancers have been identified and implicated in human disease. Defined by their magnitude of size, transcription factor density, and binding of transcriptional machinery, super-enhancers have been associated with genes driving cell differentiation. While their functions are [...] Read more.

Recently, unique areas of transcriptional regulation termed super-enhancers have been identified and implicated in human disease. Defined by their magnitude of size, transcription factor density, and binding of transcriptional machinery, super-enhancers have been associated with genes driving cell differentiation. While their functions are not completely understood, it is clear that these regions driving high-level transcription are susceptible to perturbation, and trait-associated single nucleotide polymorphisms (SNPs) occur within super-enhancers of disease-relevant cell types. Here we review evidence for super-enhancer involvement in cancers, complex diseases, and developmental disorders and discuss interactions between super-enhancers and cofactors/chromatin regulators. Full article

(This article belongs to the Special Issue Chromatin Dynamics)

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Open AccessArticle

Transcriptome Analysis of Two Vicia sativa Subspecies: Mining Molecular Markers to Enhance Genomic Resources for Vetch Improvement

by Tae-Sung Kim, Sebastin Raveendar, Sundan Suresh, Gi-An Lee, Jung-Ro Lee, Joon-Hyeong Cho, Sok-Young Lee, Kyung-Ho Ma, Gyu-Taek Cho and Jong-Wook Chung

Genes 2015, 6(4), 1164-1182; https://doi.org/10.3390/genes6041164 - 2 Nov 2015

Cited by 19 | Viewed by 5787

Abstract

The vetch (Vicia sativa) is one of the most important annual forage legumes globally due to its multiple uses and high nutritional content. Despite these agronomical benefits, many drawbacks, including cyano-alanine toxin, has reduced the agronomic value of vetch varieties. Here, [...] Read more.

The vetch (Vicia sativa) is one of the most important annual forage legumes globally due to its multiple uses and high nutritional content. Despite these agronomical benefits, many drawbacks, including cyano-alanine toxin, has reduced the agronomic value of vetch varieties. Here, we used 454 technology to sequence the two V. sativa subspecies (ssp. sativa and ssp. nigra) to enrich functional information and genetic marker resources for the vetch research community. A total of 86,532 and 47,103 reads produced 35,202 and 18,808 unigenes with average lengths of 735 and 601 bp for V. sativa sativa and V. sativa nigra, respectively. Gene Ontology annotations and the cluster of orthologous gene classes were used to annotate the function of the Vicia transcriptomes. The Vicia transcriptome sequences were then mined for simple sequence repeat (SSR) and single nucleotide polymorphism (SNP) markers. About 13% and 3% of the Vicia unigenes contained the putative SSR and SNP sequences, respectively. Among those SSRs, 100 were chosen for the validation and the polymorphism test using the Vicia germplasm set. Thus, our approach takes advantage of the utility of transcriptomic data to expedite a vetch breeding program. Full article

(This article belongs to the Special Issue Genetic Diversity for Crop Improvement)

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Open AccessArticle

COBRA-Seq: Sensitive and Quantitative Methylome Profiling

by Hilal Varinli, Aaron L. Statham, Susan J. Clark, Peter L. Molloy and Jason P. Ross

Genes 2015, 6(4), 1140-1163; https://doi.org/10.3390/genes6041140 - 23 Oct 2015

Cited by 10 | Viewed by 7704

Abstract

Combined Bisulfite Restriction Analysis (COBRA) quantifies DNA methylation at a specific locus. It does so via digestion of PCR amplicons produced from bisulfite-treated DNA, using a restriction enzyme that contains a cytosine within its recognition sequence, such as TaqI. Here, we introduce [...] Read more.

Combined Bisulfite Restriction Analysis (COBRA) quantifies DNA methylation at a specific locus. It does so via digestion of PCR amplicons produced from bisulfite-treated DNA, using a restriction enzyme that contains a cytosine within its recognition sequence, such as TaqI. Here, we introduce COBRA-seq, a genome wide reduced methylome method that requires minimal DNA input (0.1–1.0 mg) and can either use PCR or linear amplification to amplify the sequencing library. Variants of COBRA-seq can be used to explore CpG-depleted as well as CpG-rich regions in vertebrate DNA. The choice of enzyme influences enrichment for specific genomic features, such as CpG-rich promoters and CpG islands, or enrichment for less CpG dense regions such as enhancers. COBRA-seq coupled with linear amplification has the additional advantage of reduced PCR bias by producing full length fragments at high abundance. Unlike other reduced representative methylome methods, COBRA-seq has great flexibility in the choice of enzyme and can be multiplexed and tuned, to reduce sequencing costs and to interrogate different numbers of sites. Moreover, COBRA-seq is applicable to non-model organisms without the reference genome and compatible with the investigation of non-CpG methylation by using restriction enzymes containing CpA, CpT, and CpC in their recognition site. Full article

(This article belongs to the Special Issue Epigenetic Biomarkers)

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Open AccessArticle

Analysis of Codon Usage Patterns in Herbaceous Peony (Paeonia lactiflora Pall.) Based on Transcriptome Data

by Yanqing Wu, Daqiu Zhao and Jun Tao

Genes 2015, 6(4), 1125-1139; https://doi.org/10.3390/genes6041125 - 22 Oct 2015

Cited by 47 | Viewed by 6718

Abstract

Codon usage bias, which exists in many genomes, is mainly determined by mutation and selection. To elucidate the genetic features and evolutionary history of herbaceous peony (Paeonia lactiflora), a well-known symbol of prosperity in China, we examined synonymous codon usage in [...] Read more.

Codon usage bias, which exists in many genomes, is mainly determined by mutation and selection. To elucidate the genetic features and evolutionary history of herbaceous peony (Paeonia lactiflora), a well-known symbol of prosperity in China, we examined synonymous codon usage in 24,216 reconstructed genes from the P. lactiflora transcriptome. The mean GC content was 44.4%, indicating that the nucleotide content of P. lactiflora genes is slightly AT rich and GC poor. The P. lactiflora genome has a wide range of GC3 (GC content at the third synonymous codon position) distribution, with a significant correlation between GC12 and GC3. ENC (effective number of codons) analysis suggested that mutational bias played a major role in shaping codon usage. Parity Rule 2 (PR2) analysis revealed that GC and AU were not used proportionally. We identified 22 “optimal codons”, most ending with an A or U. Our results suggested that nucleotide composition mutation bias and translational selection were the main driving factors of codon usage bias in P. lactiflora. These results lay the foundation for exploring the evolutionary mechanisms and heterologous expression of functionally-important proteins in P. lactiflora. Full article

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Open AccessOpinion

How Porin Heterogeneity and Trade-Offs Affect the Antibiotic Susceptibility of Gram-Negative Bacteria

by Thomas Ferenci and Katherine Phan

Genes 2015, 6(4), 1113-1124; https://doi.org/10.3390/genes6041113 - 21 Oct 2015

Cited by 17 | Viewed by 10063

Abstract

Variations in porin proteins are common in Gram-negative pathogens. Altered or absent porins reduce access of polar antibiotics across the outer membrane and can thus contribute to antibiotic resistance. Reduced permeability has a cost however, in lowering access to nutrients. This trade-off between [...] Read more.

Variations in porin proteins are common in Gram-negative pathogens. Altered or absent porins reduce access of polar antibiotics across the outer membrane and can thus contribute to antibiotic resistance. Reduced permeability has a cost however, in lowering access to nutrients. This trade-off between permeability and nutritional competence is the source of considerable natural variation in porin gate-keeping. Mutational changes in this trade-off are frequently selected, so susceptibility to detergents and antibiotics is polymorphic in environmental isolates as well as pathogens. Understanding the mechanism, costs and heterogeneity of antibiotic exclusion by porins will be crucial in combating Gram negative infections. Full article

(This article belongs to the Special Issue Antibiotic Resistance: Mobility and Microbiomes)

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Open AccessArticle

Epigenetic Heterogeneity of B-Cell Lymphoma: Chromatin Modifiers

by Lydia Hopp, Lilit Nersisyan, Henry Löffler-Wirth, Arsen Arakelyan and Hans Binder

Genes 2015, 6(4), 1076-1112; https://doi.org/10.3390/genes6041076 - 21 Oct 2015

Cited by 15 | Viewed by 10138

Abstract

We systematically studied the expression of more than fifty histone and DNA (de)methylating enzymes in lymphoma and healthy controls. As a main result, we found that the expression levels of nearly all enzymes become markedly disturbed in lymphoma, suggesting deregulation of large parts [...] Read more.

We systematically studied the expression of more than fifty histone and DNA (de)methylating enzymes in lymphoma and healthy controls. As a main result, we found that the expression levels of nearly all enzymes become markedly disturbed in lymphoma, suggesting deregulation of large parts of the epigenetic machinery. We discuss the effect of DNA promoter methylation and of transcriptional activity in the context of mutated epigenetic modifiers such as EZH2 and MLL2. As another mechanism, we studied the coupling between the energy metabolism and epigenetics via metabolites that act as cofactors of JmjC-type demethylases. Our study results suggest that Burkitt’s lymphoma and diffuse large B-cell Lymphoma differ by an imbalance of repressive and poised promoters, which is governed predominantly by the activity of methyltransferases and the underrepresentation of demethylases in this regulation. The data further suggest that coupling of epigenetics with the energy metabolism can also be an important factor in lymphomagenesis in the absence of direct mutations of genes in metabolic pathways. Understanding of epigenetic deregulation in lymphoma and possibly in cancers in general must go beyond simple schemes using only a few modes of regulation. Full article

(This article belongs to the Special Issue Chromatin Dynamics)

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Open AccessReview

Characterization of DNA Methylation in Circulating Tumor Cells

by Constantin F. Pixberg, Wolfgang A. Schulz, Nikolas H. Stoecklein and Rui P. L. Neves

Genes 2015, 6(4), 1053-1075; https://doi.org/10.3390/genes6041053 - 21 Oct 2015

Cited by 47 | Viewed by 9731

Abstract

Epigenetics contributes to molecular mechanisms leading to tumor cell transformation and systemic progression of cancer. However, the dynamics of epigenetic remodeling during metastasis remains unexplored. In this context, circulating tumor cells (CTCs) might enable a direct insight into epigenetic mechanisms relevant for metastasis [...] Read more.

Epigenetics contributes to molecular mechanisms leading to tumor cell transformation and systemic progression of cancer. However, the dynamics of epigenetic remodeling during metastasis remains unexplored. In this context, circulating tumor cells (CTCs) might enable a direct insight into epigenetic mechanisms relevant for metastasis by providing direct access to systemic cancer. CTCs can be used as prognostic markers in cancer patients and are regarded as potential metastatic precursor cells. However, despite substantial technical progress, the detection and molecular characterization of CTCs remain challenging, in particular the analysis of DNA methylation. As recent studies have started to address the epigenetic state of CTCs, we discuss here the potential of such investigations to elucidate mechanisms of metastasis and to develop tumor biomarkers. Full article

(This article belongs to the Special Issue Epigenetic Biomarkers)

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Open AccessArticle

Transcriptome Changes during the Life Cycle of the Red Sponge, Mycale phyllophila (Porifera, Demospongiae, Poecilosclerida)

by Fan Qiu, Shaoxiong Ding, Huilong Ou, Dexiang Wang, Jun Chen and Michael M. Miyamoto

Genes 2015, 6(4), 1023-1052; https://doi.org/10.3390/genes6041023 - 20 Oct 2015

Cited by 12 | Viewed by 8060

Abstract

Sponges are an ancient metazoan group with broad ecological, evolutionary, and biotechnological importance. As in other marine invertebrates with a biphasic life cycle, the developing sponge undergoes a significant morphological, physiological, and ecological transformation during settlement and metamorphosis. In this study, we compare [...] Read more.

Sponges are an ancient metazoan group with broad ecological, evolutionary, and biotechnological importance. As in other marine invertebrates with a biphasic life cycle, the developing sponge undergoes a significant morphological, physiological, and ecological transformation during settlement and metamorphosis. In this study, we compare new transcriptome datasets for three life cycle stages of the red sponge (Mycale phyllophila) to test whether gene expression (as in the model poriferan, Amphimedon queenslandica) also varies more after settlement and metamorphosis. In contrast to A. queenslandica, we find that the transcriptome of M. phyllophila changes more during the earlier pre-competent larva/post-larva transition that spans these defining events. We also find that this transition is marked by a greater frequency of significantly up-regulated Gene Ontology terms including those for morphogenesis, differentiation, and development and that the transcriptomes of its pre-competent larvae and adult are distinct. The life cycle transcriptome variation between M. phyllophila and A. queenslandica may be due to their long separate evolutionary histories and corresponding differences in developmental rates and timing. This study now calls for new transcriptome datasets of M. phyllophila and other sponges, which will allow for tests of the generality of our life cycle expression differences and for the greater exploitation of poriferans in both basic and applied research. Full article

(This article belongs to the Section Population and Evolutionary Genetics and Genomics)

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Open AccessReview

Current and Future Prospects for Epigenetic Biomarkers of Substance Use Disorders

by Allan M. Andersen, Meeshanthini V. Dogan, Steven R.H. Beach and Robert A. Philibert

Genes 2015, 6(4), 991-1022; https://doi.org/10.3390/genes6040991 - 14 Oct 2015

Cited by 65 | Viewed by 9059

Abstract

Substance abuse has an enormous impact on economic and quality of life measures throughout the world. In more developed countries, overutilization of the most common forms of substances of abuse, alcohol and tobacco, is addressed primarily through prevention of substance use initiation and [...] Read more.

Substance abuse has an enormous impact on economic and quality of life measures throughout the world. In more developed countries, overutilization of the most common forms of substances of abuse, alcohol and tobacco, is addressed primarily through prevention of substance use initiation and secondarily through the treatment of those with substance abuse or dependence. In general, these therapeutic approaches to substance abuse are deemed effective. However, there is a broad consensus that the development of additional tools to aid diagnosis, prioritize treatment selection and monitor treatment response could have substantial impact on the effectiveness of both substance use prevention and treatment. The recent demonstrations by a number of groups that substance use exposure is associated with robust changes in DNA methylation signatures of peripheral blood cells suggests the possibility that methylation assessments of blood or saliva could find broad clinical applications. In this article, we review recent progress in epigenetic approaches to substance use assessment with a particular emphasis on smoking (and alcohol) related applications. In addition, we highlight areas, such as the epigenetics of psychostimulant, opioid and cannabis abuse, which are markedly understudied and could benefit from intensified collaborative efforts to define epigenetic biomarkers of abuse and dependence. Full article

(This article belongs to the Special Issue Epigenetic Biomarkers)

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Open AccessArticle

Hypermethylation of the VTRNA1-3 Promoter is Associated with Poor Outcome in Lower Risk Myelodysplastic Syndrome Patients

by Alexandra Søgaard Helbo, Marianne Treppendahl, Derya Aslan, Konstantinos Dimopoulos, Cecilie Nandrup-Bus, Mette Skov Holm, Mette Klarskov Andersen, Gangning Liang, Lasse Sommer Kristensen and Kirsten Grønbæk

Genes 2015, 6(4), 977-990; https://doi.org/10.3390/genes6040977 - 14 Oct 2015

Cited by 18 | Viewed by 7244

Abstract

Myelodysplastic syndrome (MDS) is a heterogeneous group of clonal hematopoietic disorders. MDS is frequently associated with deletions on chromosome 5q as well as aberrant DNA methylation patterns including hypermethylation of key tumor suppressors. We have previously shown that hypermethylation and silencing of the [...] Read more.

Myelodysplastic syndrome (MDS) is a heterogeneous group of clonal hematopoietic disorders. MDS is frequently associated with deletions on chromosome 5q as well as aberrant DNA methylation patterns including hypermethylation of key tumor suppressors. We have previously shown that hypermethylation and silencing of the non-coding RNA VTRNA2-1 are correlated with poor outcomes in acute myeloid leukemia patients. In this study, we find that VTRNA1-2 and VTRNA1-3, both located on chromosome 5q, can be regulated and silenced by promoter DNA methylation, and that the hypomethylating agent 5-aza-2-deoxycytidine causes reactivation these genes. In normal hematopoiesis, we find that vault RNAs (vtRNAs) show differential methylation between various hematopoietic cell populations, indicating that allele-specific methylation events may occur during hematopoiesis. In addition, we show that VTRNA1-3 promoter hypermethylation is frequent in lower risk MDS patients and is associated with a decreased overall survival. Full article

(This article belongs to the Special Issue Epigenetic Biomarkers)

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Open AccessReview

Impact of Chromatin on HIV Replication

by Luis M. Agosto, Matthew Gagne and Andrew J. Henderson

Genes 2015, 6(4), 957-976; https://doi.org/10.3390/genes6040957 - 30 Sep 2015

Cited by 20 | Viewed by 8149

Abstract

Chromatin influences Human Immunodeficiency Virus (HIV) integration and replication. This review highlights critical host factors that influence chromatin structure and organization and that also impact HIV integration, transcriptional regulation and latency. Furthermore, recent attempts to target chromatin associated factors to reduce the HIV [...] Read more.

Chromatin influences Human Immunodeficiency Virus (HIV) integration and replication. This review highlights critical host factors that influence chromatin structure and organization and that also impact HIV integration, transcriptional regulation and latency. Furthermore, recent attempts to target chromatin associated factors to reduce the HIV proviral load are discussed. Full article

(This article belongs to the Special Issue Chromatin Dynamics)

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Epigenetic Therapy for Solid Tumors: Highlighting the Impact of Tumor Hypoxia

by Shaliny Ramachandran, Jonathan Ient, Eva-Leonne Göttgens, Adam J. Krieg and Ester M. Hammond

Genes 2015, 6(4), 935-956; https://doi.org/10.3390/genes6040935 - 25 Sep 2015

Cited by 44 | Viewed by 11736

Abstract

In the last few decades, epigenetics has emerged as an exciting new field in development and disease, with a more recent focus towards cancer. Epigenetics has classically referred to heritable patterns of gene expression, primarily mediated through DNA methylation patterns. More recently, it [...] Read more.

In the last few decades, epigenetics has emerged as an exciting new field in development and disease, with a more recent focus towards cancer. Epigenetics has classically referred to heritable patterns of gene expression, primarily mediated through DNA methylation patterns. More recently, it has come to include the reversible chemical modification of histones and DNA that dictate gene expression patterns. Both the epigenetic up-regulation of oncogenes and downregulation of tumor suppressors have been shown to drive tumor development. Current clinical trials for cancer therapy include pharmacological inhibition of DNA methylation and histone deacetylation, with the aim of reversing these cancer-promoting epigenetic changes. However, the DNA methyltransferase and histone deacetylase inhibitors have met with less than promising results in the treatment of solid tumors. Regions of hypoxia are a common occurrence in solid tumors. Tumor hypoxia is associated with increased aggressiveness and therapy resistance, and importantly, hypoxic tumor cells have a distinct epigenetic profile. In this review, we provide a summary of the recent clinical trials using epigenetic drugs in solid tumors, discuss the hypoxia-induced epigenetic changes and highlight the importance of testing the epigenetic drugs for efficacy against the most aggressive hypoxic fraction of the tumor in future preclinical testing. Full article

(This article belongs to the Special Issue Chromatin Dynamics)

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Genes, Volume 6, Issue 4 (December 2015) – 23 articles , Pages 935-1360

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