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Volume 8
Issue 3
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Genes, Volume 8, Issue 3 (March 2017) – 21 articles

Cover Story (view full-size image): mRNA libraries derived from various tissues of adult Haliotis discus hannai were sequenced and a transcriptome database, containing a total of 15,110 (female) and 12,145 (male) genes, was successfully constructed. Notwithstanding a similar KEGG composition between sexes, both sexes had several hundreds of isoforms and sex-preferentially expressed genes. The information obtained in this study represents the significant contribution to sex-specific transcriptome resources in marine invertebrates and adds insights into further diverse genetics- and physiology-based research using abalones. View this paper
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663 KiB  
Review
Roles of CDK and DDK in Genome Duplication and Maintenance: Meiotic Singularities
by Blanca Gómez-Escoda and Pei-Yun Jenny Wu
Genes 2017, 8(3), 105; https://doi.org/10.3390/genes8030105 - 20 Mar 2017
Cited by 8 | Viewed by 7475
Abstract
Cells reproduce using two types of divisions: mitosis, which generates two daughter cells each with the same genomic content as the mother cell, and meiosis, which reduces the number of chromosomes of the parent cell by half and gives rise to four gametes. [...] Read more.
Cells reproduce using two types of divisions: mitosis, which generates two daughter cells each with the same genomic content as the mother cell, and meiosis, which reduces the number of chromosomes of the parent cell by half and gives rise to four gametes. The mechanisms that promote the proper progression of the mitotic and meiotic cycles are highly conserved and controlled. They require the activities of two types of serine-threonine kinases, the cyclin-dependent kinases (CDKs) and the Dbf4-dependent kinase (DDK). CDK and DDK are essential for genome duplication and maintenance in both mitotic and meiotic divisions. In this review, we aim to highlight how these kinases cooperate to orchestrate diverse processes during cellular reproduction, focusing on meiosis-specific adaptions of their regulation and functions in DNA metabolism.
Full article
(This article belongs to the Special Issue DNA Replication Controls)
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662 KiB  
Review
The Epigenetic Link between Prenatal Adverse Environments and Neurodevelopmental Disorders
by Marija Kundakovic and Ivana Jaric
Genes 2017, 8(3), 104; https://doi.org/10.3390/genes8030104 - 18 Mar 2017
Cited by 139 | Viewed by 14128
Abstract
Prenatal adverse environments, such as maternal stress, toxicological exposures, and viral infections, can disrupt normal brain development and contribute to neurodevelopmental disorders, including schizophrenia, depression, and autism. Increasing evidence shows that these short- and long-term effects of prenatal exposures on brain structure and [...] Read more.
Prenatal adverse environments, such as maternal stress, toxicological exposures, and viral infections, can disrupt normal brain development and contribute to neurodevelopmental disorders, including schizophrenia, depression, and autism. Increasing evidence shows that these short- and long-term effects of prenatal exposures on brain structure and function are mediated by epigenetic mechanisms. Animal studies demonstrate that prenatal exposure to stress, toxins, viral mimetics, and drugs induces lasting epigenetic changes in the brain, including genes encoding glucocorticoid receptor (Nr3c1) and brain-derived neurotrophic factor (Bdnf). These epigenetic changes have been linked to changes in brain gene expression, stress reactivity, and behavior, and often times, these effects are shown to be dependent on the gestational window of exposure, sex, and exposure level. Although evidence from human studies is more limited, gestational exposure to environmental risks in humans is associated with epigenetic changes in peripheral tissues, and future studies are required to understand whether we can use peripheral biomarkers to predict neurobehavioral outcomes. An extensive research effort combining well-designed human and animal studies, with comprehensive epigenomic analyses of peripheral and brain tissues over time, will be necessary to improve our understanding of the epigenetic basis of neurodevelopmental disorders. Full article
(This article belongs to the Special Issue Role of Epigenetic Gene Regulation in Brain Function)
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4169 KiB  
Article
The Complete Chloroplast Genome Sequences of Six Rehmannia Species
by Shuyun Zeng, Tao Zhou, Kai Han, Yanci Yang, Jianhua Zhao and Zhan-Lin Liu
Genes 2017, 8(3), 103; https://doi.org/10.3390/genes8030103 - 15 Mar 2017
Cited by 67 | Viewed by 7747
Abstract
Rehmannia is a non-parasitic genus in Orobanchaceae including six species mainly distributed in central and north China. Its phylogenetic position and infrageneric relationships remain uncertain due to potential hybridization and polyploidization. In this study, we sequenced and compared the complete chloroplast genomes of [...] Read more.
Rehmannia is a non-parasitic genus in Orobanchaceae including six species mainly distributed in central and north China. Its phylogenetic position and infrageneric relationships remain uncertain due to potential hybridization and polyploidization. In this study, we sequenced and compared the complete chloroplast genomes of six Rehmannia species using Illumina sequencing technology to elucidate the interspecific variations. Rehmannia plastomes exhibited typical quadripartite and circular structures with good synteny of gene order. The complete genomes ranged from 153,622 bp to 154,055 bp in length, including 133 genes encoding 88 proteins, 37 tRNAs, and 8 rRNAs. Three genes (rpoA, rpoC2, accD) have potentially experienced positive selection. Plastome size variation of Rehmannia was mainly ascribed to the expansion and contraction of the border regions between the inverted repeat (IR) region and the single-copy (SC) regions. Despite of the conserved structure in Rehmannia plastomes, sequence variations provide useful phylogenetic information. Phylogenetic trees of 23 Lamiales species reconstructed with the complete plastomes suggested that Rehmannia was monophyletic and sister to the clade of Lindenbergia and the parasitic taxa in Orobanchaceae. The interspecific relationships within Rehmannia were completely different with the previous studies. In future, population phylogenomic works based on plastomes are urgently needed to clarify the evolutionary history of Rehmannia. Full article
(This article belongs to the Section Plant Genetics and Genomics)
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3012 KiB  
Article
Alternative Splicing Profile and Sex-Preferential Gene Expression in the Female and Male Pacific Abalone Haliotis discus hannai
by Mi Ae Kim, Jae-Sung Rhee, Tae Ha Kim, Jung Sick Lee, Ah-Young Choi, Beom-Soon Choi, Ik-Young Choi and Young Chang Sohn
Genes 2017, 8(3), 99; https://doi.org/10.3390/genes8030099 - 9 Mar 2017
Cited by 36 | Viewed by 11541
Abstract
In order to characterize the female or male transcriptome of the Pacific abalone and further increase genomic resources, we sequenced the mRNA of full-length complementary DNA (cDNA) libraries derived from pooled tissues of female and male Haliotis discus hannai by employing the Iso-Seq [...] Read more.
In order to characterize the female or male transcriptome of the Pacific abalone and further increase genomic resources, we sequenced the mRNA of full-length complementary DNA (cDNA) libraries derived from pooled tissues of female and male Haliotis discus hannai by employing the Iso-Seq protocol of the PacBio RSII platform. We successfully assembled whole full-length cDNA sequences and constructed a transcriptome database that included isoform information. After clustering, a total of 15,110 and 12,145 genes that coded for proteins were identified in female and male abalones, respectively. A total of 13,057 putative orthologs were retained from each transcriptome in abalones. Overall Gene Ontology terms and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways analyzed in each database showed a similar composition between sexes. In addition, a total of 519 and 391 isoforms were genome-widely identified with at least two isoforms from female and male transcriptome databases. We found that the number of isoforms and their alternatively spliced patterns are variable and sex-dependent. This information represents the first significant contribution to sex-preferential genomic resources of the Pacific abalone. The availability of whole female and male transcriptome database and their isoform information will be useful to improve our understanding of molecular responses and also for the analysis of population dynamics in the Pacific abalone. Full article
(This article belongs to the Section Population and Evolutionary Genetics and Genomics)
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593 KiB  
Article
A Frameshift Mutation in KIT is Associated with  White Spotting in the Arabian Camel
by Heather Holl, Ramiro Isaza, Yasmin Mohamoud, Ayeda Ahmed, Faisal Almathen, Cherifi Youcef, Semir Gaouar, Douglas F. Antczak and Samantha Brooks
Genes 2017, 8(3), 102; https://doi.org/10.3390/genes8030102 - 9 Mar 2017
Cited by 26 | Viewed by 7784
Abstract
While the typical Arabian camel is characterized by a single colored coat, there are rare populations with white spotting patterns. White spotting coat patterns are found in virtually all domesticated species, but are rare in wild species. Theories suggest that white spotting is [...] Read more.
While the typical Arabian camel is characterized by a single colored coat, there are rare populations with white spotting patterns. White spotting coat patterns are found in virtually all domesticated species, but are rare in wild species. Theories suggest that white spotting is linked to the domestication process, and is occasionally associated with health disorders. Though mutations have been found in a diverse array of species, fewer than 30 genes have been associated with spotting patterns, thus providing a key set of candidate genes for the Arabian camel. We obtained 26 spotted camels and 24 solid controls for candidate gene analysis. One spotted and eight solid camels were whole genome sequenced as part of a separate project. The spotted camel was heterozygous for a frameshift deletion in KIT (c.1842delG, named KITW1 for White spotting 1), whereas all other camels were wild‐type (KIT+/KIT+). No additional mutations unique to the spotted camel were detected in the EDNRB, EDN3, SOX10, KITLG, PDGFRA, MITF, and PAX3 candidate white spotting genes. Sanger sequencing of the study population identified an additional five kITW1/KIT+ spotted camels. The frameshift results in a premature stop codon five amino acids downstream, thus terminating KIT at the tyrosine kinase domain. An additional 13 spotted camels tested KIT+/KIT+, but due to phenotypic differences when compared to the KITW1/KIT+ camels, they likely represent an independent mutation. Our study suggests that there are at least two causes of white spotting in the Arabian camel, the newly described KITW1 allele and an uncharacterized mutation. Full article
(This article belongs to the Section Molecular Genetics and Genomics)
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3614 KiB  
Review
The Diabetes-Linked Transcription Factor PAX4: From Gene to Functional Consequences
by Petra I. Lorenzo, Francisco Juárez-Vicente, Nadia Cobo-Vuilleumier, Mario García-Domínguez and Benoit R. Gauthier
Genes 2017, 8(3), 101; https://doi.org/10.3390/genes8030101 - 9 Mar 2017
Cited by 31 | Viewed by 9243
Abstract
Paired box 4 (PAX4) is a key factor in the generation of insulin producing β-cells during embryonic development. In adult islets, PAX4 expression is sequestered to a subset of β-cells that are prone to proliferation and more resistant to stress-induced apoptosis. The importance [...] Read more.
Paired box 4 (PAX4) is a key factor in the generation of insulin producing β-cells during embryonic development. In adult islets, PAX4 expression is sequestered to a subset of β-cells that are prone to proliferation and more resistant to stress-induced apoptosis. The importance of this transcription factor for adequate pancreatic islets functionality has been manifested by the association of mutations in PAX4 with the development of diabetes, independently of its etiology. Overexpression of this factor in adult islets stimulates β-cell proliferation and increases their resistance to apoptosis. Additionally, in an experimental model of autoimmune diabetes, a novel immunomodulatory function for this factor has been suggested. Altogether these data pinpoint at PAX4 as an important target for novel regenerative therapies for diabetes treatment, aiming at the preservation of the remaining β-cells in parallel to the stimulation of their proliferation to replenish the β-cell mass lost during the progression of the disease. However, the adequate development of such therapies requires the knowledge of the molecular mechanisms controlling the expression of PAX4 as well as the downstream effectors that could account for PAX4 action. Full article
(This article belongs to the Special Issue Genetics and Functional Genomics of Diabetes Mellitus)
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943 KiB  
Communication
Development of Gene‐Based SSR Markers in Winged  Bean (Psophocarpus tetragonolobus (L.) DC.) for  Diversity Assessment
by Quin Nee Wong, Alberto Stefano Tanzi, Wai Kuan Ho, Sunir Malla, Martin Blythe, Asha Karunaratne, Festo Massawe and Sean Mayes
Genes 2017, 8(3), 100; https://doi.org/10.3390/genes8030100 - 9 Mar 2017
Cited by 33 | Viewed by 6727
Abstract
Winged bean (Psophocarpus tetragonolobus) is an herbaceous multipurpose legume grown in hot and humid countries as a pulse, vegetable (leaves and pods), or root tuber crop depending on local consumption preferences. In addition to its different nutrient‐rich edible parts which could contribute to [...] Read more.
Winged bean (Psophocarpus tetragonolobus) is an herbaceous multipurpose legume grown in hot and humid countries as a pulse, vegetable (leaves and pods), or root tuber crop depending on local consumption preferences. In addition to its different nutrient‐rich edible parts which could contribute to food and nutritional security, it is an efficient nitrogen fixer as a component of sustainable agricultural systems. Generating genetic resources and improved lines would help to accelerate the breeding improvement of this crop, as the lack of improved cultivars adapted to specific environments has been one of the limitations preventing wider use. A transcriptomic de novo assembly was constructed from four tissues: leaf, root, pod, and reproductive tissues from Malaysian accessions, comprising of 198,554 contigs with a N50 of 1462 bp. Of these, 138,958 (70.0%) could be annotated. Among 9682 genic simple sequence repeat (SSR) motifs identified (excluding monomer repeats), trinucleotide‐repeats were the most abundant (4855), followed by di‐nucleotide (4500) repeats. A total of 18 SSR markers targeting di‐ and tri‐nucleotide repeats have been validated as polymorphic markers based on an initial assessment of nine genotypes originated from five countries. A cluster analysis revealed provisional clusters among this limited, yet diverse selection of germplasm. The developed assembly and validated genic SSRs in this study provide a foundation for a better understanding of the plant breeding system for the genetic improvement of winged bean. Full article
(This article belongs to the Section Plant Genetics and Genomics)
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2130 KiB  
Review
Regulation of DNA Replication through Natural  Impediments in the Eukaryotic Genome
by Mariana C. Gadaleta and Eishi Noguchi
Genes 2017, 8(3), 98; https://doi.org/10.3390/genes8030098 - 7 Mar 2017
Cited by 41 | Viewed by 13833
Abstract
All living organisms need to duplicate their genetic information while protecting it from unwanted mutations, which can lead to genetic disorders and cancer development. Inaccuracies during DNA replication are the major cause of genomic instability, as replication forks are prone to stalling and [...] Read more.
All living organisms need to duplicate their genetic information while protecting it from unwanted mutations, which can lead to genetic disorders and cancer development. Inaccuracies during DNA replication are the major cause of genomic instability, as replication forks are prone to stalling and collapse, resulting in DNA damage. The presence of exogenous DNA damaging agents as well as endogenous difficult‐to‐replicate DNA regions containing DNA–protein complexes, repetitive DNA, secondary DNA structures, or transcribing RNA polymerases, increases the risk of genomic instability and thus threatens cell survival. Therefore, understanding the cellular mechanisms required to preserve the genetic information during S phase is of paramount importance. In this review, we will discuss our current understanding of how cells cope with these natural impediments in order to prevent DNA damage and genomic instability during DNA replication. Full article
(This article belongs to the Special Issue DNA Replication Controls)
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5743 KiB  
Article
c‐Myc‐Induced Survivin Is Essential for Promoting  the Notch‐Dependent T Cell Differentiation from  Hematopoietic Stem Cells
by Rizwanul Haque, Jianyong Song, Mohammad Haque, Fengyang Lei, Praneet Sandhu, Bing Ni, Songguo Zheng, Deyu Fang, Jin‐Ming Yang and Jianxun Song
Genes 2017, 8(3), 97; https://doi.org/10.3390/genes8030097 - 6 Mar 2017
Cited by 14 | Viewed by 6851
Abstract
Notch is indispensable for T cell lineage commitment, and is needed for thymocyte differentiation at early phases. During early stages of T cell development, active Notch prevents other lineage potentials including B cell lineage and myeloid cell (e.g., dendritic cell) lineage. Nevertheless, the [...] Read more.
Notch is indispensable for T cell lineage commitment, and is needed for thymocyte differentiation at early phases. During early stages of T cell development, active Notch prevents other lineage potentials including B cell lineage and myeloid cell (e.g., dendritic cell) lineage. Nevertheless, the precise intracellular signaling pathways by which Notch promotes T cell differentiation remain unclear. Here we report that the transcription factor c‐Myc is a key mediator of the Notch signaling–regulated T cell differentiation. In a well‐established in vitro differentiation model of T lymphocytes from hematopoietic stem cells, we showed that Notch1 and 4 directly promoted c‐Myc expression; dominant‐negative (DN) c‐Myc inhibited early T cell differentiation. Moreover, the c‐Myc expression activated by Notch signaling increased the expression of survivin, an inhibitor of apoptosis (IAP) protein. We further demonstrated that over‐expression of c‐Myc increased the abundance of survivin and the T cell differentiation thereof, whereas dn c‐Myc reduced survivin levels and concomitantly retarded the differentiation. The c‐Myc–dependent survivin induction is functionally germane, because Notch‐dependent T cell differentiation was canceled by the depletion of survivin. These results identify both c‐Myc and survivin as important mediators of the Notch signaling–regulated differentiation of T lymphocytes from hematopoietic stem cells. Full article
(This article belongs to the Special Issue MYC Networks)
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2184 KiB  
Article
Neurotoxic Doses of Chronic Methamphetamine  Trigger Retrotransposition of the Identifier Element  in Rat Dorsal Dentate Gyrus
by Anna Moszczynska, Kyle J. Burghardt and Dongyue Yu
Genes 2017, 8(3), 96; https://doi.org/10.3390/genes8030096 - 6 Mar 2017
Cited by 4 | Viewed by 6140
Abstract
Short interspersed elements (SINEs) are typically silenced by DNA hypermethylation in somatic cells, but can retrotranspose in proliferating cells during adult neurogenesis. Hypomethylation caused by disease pathology or genotoxic stress leads to genomic instability of SINEs. The goal of the present investigation was [...] Read more.
Short interspersed elements (SINEs) are typically silenced by DNA hypermethylation in somatic cells, but can retrotranspose in proliferating cells during adult neurogenesis. Hypomethylation caused by disease pathology or genotoxic stress leads to genomic instability of SINEs. The goal of the present investigation was to determine whether neurotoxic doses of binge or chronic methamphetamine (METH) trigger retrotransposition of the identifier (ID) element, a member of the rat SINE family, in the dentate gyrus genomic DNA. Adult male Sprague‐Dawley rats were treated with saline or high doses of binge or chronic METH and sacrificed at three different time points thereafter. DNA methylation analysis, immunohistochemistry and next‐generation sequencing (NGS) were performed on the dorsal dentate gyrus samples. Binge METH triggered hypomethylation, while chronic METH triggered hypermethylation of the CpG‐2 site. Both METH regimens were associated with increased intensities in poly(A)‐binding protein 1 (PABP1, a SINE regulatory protein)‐like immunohistochemical staining in the dentate gyrus. The amplification of several ID element sequences was significantly higher in the chronic METH group than in the control group a week after METH, and they mapped to genes coding for proteins regulating cell growth and proliferation, transcription, protein function as well as for a variety of transporters. The results suggest that chronic METH induces ID element retrotransposition in the dorsal dentate gyrus and may affect hippocampal neurogenesis. Full article
(This article belongs to the Special Issue Role of Epigenetic Gene Regulation in Brain Function)
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635 KiB  
Review
Influence of microRNAs and Long Non-Coding RNAs in Cancer Chemoresistance
by Duncan Ayers and Jo Vandesompele
Genes 2017, 8(3), 95; https://doi.org/10.3390/genes8030095 - 3 Mar 2017
Cited by 96 | Viewed by 10064
Abstract
Innate and acquired chemoresistance exhibited by most tumours exposed to conventional chemotherapeutic agents account for the majority of relapse cases in cancer patients. Such chemoresistance phenotypes are of a multi-factorial nature from multiple key molecular players. The discovery of the RNA interference pathway [...] Read more.
Innate and acquired chemoresistance exhibited by most tumours exposed to conventional chemotherapeutic agents account for the majority of relapse cases in cancer patients. Such chemoresistance phenotypes are of a multi-factorial nature from multiple key molecular players. The discovery of the RNA interference pathway in 1998 and the widespread gene regulatory influences exerted by microRNAs (miRNAs) and other non-coding RNAs have certainly expanded the level of intricacy present for the development of any single physiological phenotype, including cancer chemoresistance. This review article focuses on the latest research efforts in identifying and validating specific key molecular players from the two main families of non-coding RNAs, namely miRNAs and long non-coding RNAs (lncRNAs), having direct or indirect influences in the development of cancer drug resistance properties and how such knowledge can be utilised for novel theranostics in oncology. Full article
(This article belongs to the Special Issue microRNAs and Other Non-Coding RNAs in Human Diseases)
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3720 KiB  
Article
Antisense Oligonucleotides Used to Target the DUX4 mRNA as Therapeutic Approaches in FaciosScapuloHumeral Muscular Dystrophy (FSHD)
by Eugénie Ansseau, Céline Vanderplanck, Armelle Wauters, Scott Q. Harper, Frédérique Coppée and Alexandra Belayew
Genes 2017, 8(3), 93; https://doi.org/10.3390/genes8030093 - 3 Mar 2017
Cited by 52 | Viewed by 10971
Abstract
FacioScapuloHumeral muscular Dystrophy (FSHD) is one of the most prevalent hereditary myopathies and is generally characterized by progressive muscle atrophy affecting the face, scapular fixators; upper arms and distal lower legs. The FSHD locus maps to a macrosatellite D4Z4 repeat array on chromosome [...] Read more.
FacioScapuloHumeral muscular Dystrophy (FSHD) is one of the most prevalent hereditary myopathies and is generally characterized by progressive muscle atrophy affecting the face, scapular fixators; upper arms and distal lower legs. The FSHD locus maps to a macrosatellite D4Z4 repeat array on chromosome 4q35. Each D4Z4 unit contains a DUX4 gene; the most distal of which is flanked by a polyadenylation site on FSHD-permissive alleles, which allows for production of stable DUX4 mRNAs. In addition, an open chromatin structure is required for DUX4 gene transcription. FSHD thus results from a gain of function of the toxic DUX4 protein that normally is only expressed in germ line and stem cells. Therapeutic strategies are emerging that aim to decrease DUX4 expression or toxicity in FSHD muscle cells. We review here the heterogeneity of DUX4 mRNAs observed in muscle and stem cells; and the use of antisense oligonucleotides (AOs) targeting the DUX4 mRNA to interfere either with transcript cleavage/polyadenylation or intron splicing. We show in primary cultures that DUX4-targeted AOs suppress the atrophic FSHD myotube phenotype; but do not improve the disorganized FSHD myotube phenotype which could be caused by DUX4c over-expression. Thus; DUX4c might constitute another therapeutic target in FSHD. Full article
(This article belongs to the Special Issue Therapeutic Alternative Splicing: Mechanisms and Applications)
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145 KiB  
Erratum
Erratum: Gu, S. et al. Error-Free Bypass of 7,8-dihydro-8-oxo-2′-deoxyguanosine by DNA Polymerase of Pseudomonas aeruginosa Phage PaP1. Genes 2017, 8, 18
by Shiling Gu, Qizhen Xue, Qin Liu, Mei Xiong, Wanneng Wang and Huidong Zhang
Genes 2017, 8(3), 91; https://doi.org/10.3390/genes8030091 - 3 Mar 2017
Viewed by 3421
Abstract
n/a Full article
(This article belongs to the Special Issue DNA Replication Controls)
618 KiB  
Review
Gold Nanoparticle Approach to the Selective Delivery of Gene Silencing in Cancer—The Case for Combined Delivery?
by Rita Mendes, Alexandra R. Fernandes and Pedro V. Baptista
Genes 2017, 8(3), 94; https://doi.org/10.3390/genes8030094 - 2 Mar 2017
Cited by 80 | Viewed by 9925
Abstract
Gene therapy arises as a great promise for cancer therapeutics due to its potential to silence genes involved in tumor development. In fact, there are some pivotal gene drivers that suffer critical alterations leading to cell transformation and ultimately to tumor growth. In [...] Read more.
Gene therapy arises as a great promise for cancer therapeutics due to its potential to silence genes involved in tumor development. In fact, there are some pivotal gene drivers that suffer critical alterations leading to cell transformation and ultimately to tumor growth. In this vein, gene silencing has been proposed as an active tool to selectively silence these molecular triggers of cancer, thus improving treatment. However, naked nucleic acid (DNA/RNA) sequences are reported to have a short lifetime in the body, promptly degraded by circulating enzymes, which in turn speed up elimination and decrease the therapeutic potential of these drugs. The use of nanoparticles for the effective delivery of these silencers to the specific target locations has allowed researchers to overcome this issue. Particularly, gold nanoparticles (AuNPs) have been used as attractive vehicles for the target-specific delivery of gene-silencing moieties, alone or in combination with other drugs. We shall discuss current trends in AuNP-based delivery of gene-silencing tools, considering the promising road ahead without overlooking existing concerns for their translation to clinics. Full article
(This article belongs to the Section Human Genomics and Genetic Diseases)
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988 KiB  
Review
The Role of the Transcriptional Response to DNA Replication Stress
by Anna E. Herlihy and Robertus A.M. De Bruin
Genes 2017, 8(3), 92; https://doi.org/10.3390/genes8030092 - 2 Mar 2017
Cited by 16 | Viewed by 8736
Abstract
During DNA replication many factors can result in DNA replication stress. The DNA replication stress checkpoint prevents the accumulation of replication stress-induced DNA damage and the potential ensuing genome instability. A critical role for post-translational modifications, such as phosphorylation, in the replication stress [...] Read more.
During DNA replication many factors can result in DNA replication stress. The DNA replication stress checkpoint prevents the accumulation of replication stress-induced DNA damage and the potential ensuing genome instability. A critical role for post-translational modifications, such as phosphorylation, in the replication stress checkpoint response has been well established. However, recent work has revealed an important role for transcription in the cellular response to DNA replication stress. In this review, we will provide an overview of current knowledge of the cellular response to DNA replication stress with a specific focus on the DNA replication stress checkpoint transcriptional response and its role in the prevention of replication stress-induced DNA damage. Full article
(This article belongs to the Special Issue DNA Replication Controls)
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1374 KiB  
Article
Rapid Sampling of Escherichia coli After Changing Oxygen Conditions Reveals Transcriptional Dynamics
by Joachim Von Wulffen, Andreas Ulmer, Günter Jäger, Oliver Sawodny and Ronny Feuer
Genes 2017, 8(3), 90; https://doi.org/10.3390/genes8030090 - 28 Feb 2017
Cited by 14 | Viewed by 6375
Abstract
Escherichia coli is able to shift between anaerobic and aerobic metabolism by adapting its gene expression, e.g., of metabolic genes, to the new environment. The dynamics of gene expression that result from environmental shifts are limited, amongst others, by the time needed for [...] Read more.
Escherichia coli is able to shift between anaerobic and aerobic metabolism by adapting its gene expression, e.g., of metabolic genes, to the new environment. The dynamics of gene expression that result from environmental shifts are limited, amongst others, by the time needed for regulation and transcription elongation. In this study, we examined gene expression dynamics after an anaerobic-to-aerobic shift on a short time scale (0.5, 1, 2, 5, and 10 min) by RNA sequencing with emphasis on delay times and transcriptional elongation rates (TER). Transient expression patterns and timing of differential expression, characterized by delay and elongation, were identified as key features of the dataset. Gene ontology enrichment analysis revealed early upregulation of respiratory and iron-related gene sets. We inferred specific TERs of 89 operons with a mean TER of 42.0 nt/s and mean delay time of 22.4 s. TERs correlate with sequence features, such as codon bias, whereas delay times correlate with the involvement of regulators. The presented data illustrate that at very short times after a shift in oxygenation, extensional changes of the transcriptome, such as temporary responses, can be observed. Besides regulation, TERs contribute to the dynamics of gene expression. Full article
(This article belongs to the Section Microbial Genetics and Genomics)
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209 KiB  
Review
Epigenetics in Stroke Recovery
by Haifa Kassis, Amjad Shehadah, Michael Chopp and Zheng Gang Zhang
Genes 2017, 8(3), 89; https://doi.org/10.3390/genes8030089 - 27 Feb 2017
Cited by 30 | Viewed by 5390
Abstract
Abstract: While the death rate from stroke has continually decreased due to interventions in the hyperacute stage of the disease, long-term disability and institutionalization have become common sequelae in the aftermath of stroke. Therefore, identification of new molecular pathways that could be targeted [...] Read more.
Abstract: While the death rate from stroke has continually decreased due to interventions in the hyperacute stage of the disease, long-term disability and institutionalization have become common sequelae in the aftermath of stroke. Therefore, identification of new molecular pathways that could be targeted to improve neurological recovery among survivors of stroke is crucial. Epigenetic mechanisms such as post-translational modifications of histone proteins and microRNAs have recently emerged as key regulators of the enhanced plasticity observed during repair processes after stroke. In this review, we highlight the recent advancements in the evolving field of epigenetics in stroke recovery. Full article
(This article belongs to the Special Issue Role of Epigenetic Gene Regulation in Brain Function)
1058 KiB  
Review
MYC in Regulating Immunity: Metabolism and Beyond
by J.N. Rashida Gnanaprakasam and Ruoning Wang
Genes 2017, 8(3), 88; https://doi.org/10.3390/genes8030088 - 25 Feb 2017
Cited by 66 | Viewed by 12987
Abstract
Myelocytomatosis oncogene (MYC) family members, including cellular MYC (c-Myc), neuroblastoma derived MYC (MYCN), and lung carcinoma derived MYC (MYCL), have all been implicated as key oncogenic drivers in a broad range of human cancers. Beyond cancer, MYC plays an important role in other [...] Read more.
Myelocytomatosis oncogene (MYC) family members, including cellular MYC (c-Myc), neuroblastoma derived MYC (MYCN), and lung carcinoma derived MYC (MYCL), have all been implicated as key oncogenic drivers in a broad range of human cancers. Beyond cancer, MYC plays an important role in other physiological and pathological processes, namely immunity and immunological diseases. MYC largely functions as a transcription factor that promotes the expression of numerous target genes to coordinate death, proliferation, and metabolism at the cellular, tissue, and organismal levels. It has been shown that the expression of MYC family members is tightly regulated in immune cells during development or upon immune stimulations. Emerging evidence suggests that MYC family members play essential roles in regulating the development, differentiation and activation of immune cells. Through driving the expression of a broad range of metabolic genes in immune cells, MYC family members coordinate metabolic programs to support immune functions. Here, we discuss our understanding of MYC biology in immune system and how modulation of MYC impacts immune metabolism and responses. Full article
(This article belongs to the Special Issue MYC Networks)
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1696 KiB  
Review
Targeting Splicing in the Treatment of Human Disease
by Marc Suñé-Pou, Silvia Prieto-Sánchez, Sofía Boyero-Corral, Cristina Moreno-Castro, Younes El Yousfi, Josep Mª Suñé-Negre, Cristina Hernández-Munain and Carlos Suñé
Genes 2017, 8(3), 87; https://doi.org/10.3390/genes8030087 - 24 Feb 2017
Cited by 40 | Viewed by 14856
Abstract
The tightly regulated process of precursor messenger RNA (pre-mRNA) alternative splicing (AS) is a key mechanism in the regulation of gene expression. Defects in this regulatory process affect cellular functions and are the cause of many human diseases. Recent advances in our understanding [...] Read more.
The tightly regulated process of precursor messenger RNA (pre-mRNA) alternative splicing (AS) is a key mechanism in the regulation of gene expression. Defects in this regulatory process affect cellular functions and are the cause of many human diseases. Recent advances in our understanding of splicing regulation have led to the development of new tools for manipulating splicing for therapeutic purposes. Several tools, including antisense oligonucleotides and trans-splicing, have been developed to target and alter splicing to correct misregulated gene expression or to modulate transcript isoform levels. At present, deregulated AS is recognized as an important area for therapeutic intervention. Here, we summarize the major hallmarks of the splicing process, the clinical implications that arise from alterations in this process, and the current tools that can be used to deliver, target, and correct deficiencies of this key pre-mRNA processing event. Full article
(This article belongs to the Special Issue Therapeutic Alternative Splicing: Mechanisms and Applications)
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Article
Systematic Identification and Assessment of Therapeutic Targets for Breast Cancer Based on Genome-Wide RNA Interference Transcriptomes
by Yang Liu, Xiaoyao Yin, Jing Zhong, Naiyang Guan, Zhigang Luo, Lishan Min, Xing Yao, Xiaochen Bo, Licheng Dai and Hui Bai
Genes 2017, 8(3), 86; https://doi.org/10.3390/genes8030086 - 24 Feb 2017
Cited by 10 | Viewed by 6373
Abstract
With accumulating public omics data, great efforts have been made to characterize the genetic heterogeneity of breast cancer. However, identifying novel targets and selecting the best from the sizeable lists of candidate targets is still a key challenge for targeted therapy, largely owing [...] Read more.
With accumulating public omics data, great efforts have been made to characterize the genetic heterogeneity of breast cancer. However, identifying novel targets and selecting the best from the sizeable lists of candidate targets is still a key challenge for targeted therapy, largely owing to the lack of economical, efficient and systematic discovery and assessment to prioritize potential therapeutic targets. Here, we describe an approach that combines the computational evaluation and objective, multifaceted assessment to systematically identify and prioritize targets for biological validation and therapeutic exploration. We first establish the reference gene expression profiles from breast cancer cell line MCF7 upon genome-wide RNA interference (RNAi) of a total of 3689 genes, and the breast cancer query signatures using RNA-seq data generated from tissue samples of clinical breast cancer patients in the Cancer Genome Atlas (TCGA). Based on gene set enrichment analysis, we identified a set of 510 genes that when knocked down could significantly reverse the transcriptome of breast cancer state. We then perform multifaceted assessment to analyze the gene set to prioritize potential targets for gene therapy. We also propose drug repurposing opportunities and identify potentially druggable proteins that have been poorly explored with regard to the discovery of small-molecule modulators. Finally, we obtained a small list of candidate therapeutic targets for four major breast cancer subtypes, i.e., luminal A, luminal B, HER2+ and triple negative breast cancer. This RNAi transcriptome-based approach can be a helpful paradigm for relevant researches to identify and prioritize candidate targets for experimental validation. Full article
(This article belongs to the Special Issue RNA Interference 2016)
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Review
Historical and Clinical Experiences of Gene Therapy for Solid Cancers in China
by Bo Li, Ning Gao, Zhuang Zhang, Qian‐Ming Chen, Long‐Jiang Li and Yi Li
Genes 2017, 8(3), 85; https://doi.org/10.3390/genes8030085 - 24 Feb 2017
Cited by 7 | Viewed by 6628
Abstract
Based on the theoretical and clinical development of modern medicines, gene therapy has been a promising treatment strategy for cancer and other diseases. The practice of gene therapy is nearly 27 years old, since the first authorized gene transfer study took place at [...] Read more.
Based on the theoretical and clinical development of modern medicines, gene therapy has been a promising treatment strategy for cancer and other diseases. The practice of gene therapy is nearly 27 years old, since the first authorized gene transfer study took place at the National Institute of Health in 1989. However, gene therapy was not readily adopted worldwide, until recently. Several gene therapy clinical trials have been carried out in China since 1998, and medical research in China has flourished. In this report, we review the history of gene therapy in China, focusing on treatment protocol, the administration cycle, dosage calculation, and the evaluation of therapeutic effects, in order to provide more information for the additional development of this promising treatment strategy. Full article
(This article belongs to the Special Issue Gene Therapy)
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