Genes — Open Access Genetics & Genomics Journal

B cell lymphomas mainly arise from different developmental stages of B cells in germinal centers of secondary lymphoid tissue. There are a number of signaling pathways that affect the initiation and development of B cell lymphomagenesis. The functions of several key proteins that represent branching points of signaling networks are changed because of their aberrant expression, degradation, and/or accumulation, and those events determine the fate of the affected B cells. One of the most influential transcription factors, commonly associated with unfavorable prognosis for patients with B cell lymphoma, is nuclear phosphoprotein MYC. During B cell lymphomagenesis, oncogenic MYC variant is deregulated through various mechanisms, such as gene translocation, gene amplification, and epigenetic deregulation of its expression. Owing to alterations of downstream signaling cascades, MYC-overexpressing neoplastic B cells proliferate rapidly, avoid apoptosis, and become unresponsive to most conventional treatments. This review will summarize the roles of MYC in B cell development and oncogenesis, as well as its significance for current B cell lymphoma classification. We compared communication networks within transformed B cells in different lymphomas affected by overexpressed MYC and conducted a meta-analysis concerning the association of MYC with tumor prognosis in different patient populations. Full article

Abstract:MYC is a critical growth regulatory gene that is commonly overexpressed in a wide range of cancers. Therapeutic targeting of MYC transcriptional activity has long been a goal, but it has been difficult to achieve with drugs that directly block its DNA-binding ability. Additional approaches that exploit oncogene addiction are promising strategies against MYC-driven cancers. Also, drugs that target metabolic regulatory pathways and enzymes have potential for indirectly reducing MYC levels. Glucose metabolism and oxidative phosphorylation, which can be targeted by multiple agents, promote cell growth and MYC expression. Likewise, modulation of the signaling pathways and protein synthesis regulated by adenosine monophosphate-activated protein kinase (AMPK) and mechanistic target of rapamycin (mTOR) can also be an effective route for suppressing MYC translation. Furthermore, recent data suggest that metabolism of nucleotides, fatty acids and glutamine are exploited to alter MYC levels. Combination therapies offer potential new approaches to overcome metabolic plasticity caused by single agents. Although potential toxicities must be carefully controlled, new inhibitors currently being tested in clinical trials offer significant promise. Therefore, as both a downstream target of metabolism and an upstream regulator, MYC is a prominent central regulator of cancer metabolism. Exploiting metabolic vulnerabilities of MYC-driven cancers is an emerging research area with translational potential. Full article

MYCN is a member of the MYC family of proto-oncogenes. It encodes a transcription factor, MYCN, involved in the control of fundamental processes during embryonal development. The MYCN protein is situated downstream of several signaling pathways promoting cell growth, proliferation and metabolism of progenitor cells in different developing organs and tissues. Conversely, deregulated MYCN signaling supports the development of several different tumors, mainly with a childhood onset, including neuroblastoma, medulloblastoma, rhabdomyosarcoma and Wilms’ tumor, but it is also associated with some cancers occurring during adulthood such as prostate and lung cancer. In neuroblastoma, MYCN-amplification is the most consistent genetic aberration associated with poor prognosis and treatment failure. Targeting MYCN has been proposed as a therapeutic strategy for the treatment of these tumors and great efforts have allowed the development of direct and indirect MYCN inhibitors with potential clinical use. Full article

Genetic information is faithfully copied by DNA replication through many rounds of cell division. In mammals, DNA is replicated in Mb-sized chromosomal units called “replication domains.” While genome-wide maps in multiple cell types and disease states have uncovered both dynamic and static properties of replication domains, we are still in the process of understanding the mechanisms that give rise to these properties. A better understanding of the molecular basis of replication domain regulation will bring new insights into chromosome structure and function. Full article

Sucrose synthase (SS) is widely considered as the key enzyme involved in the plant sugar metabolism that is critical to plant growth and development, especially quality of the fruit. The members of SS gene family have been identified and characterized in multiple plant genomes. However, detailed information about this gene family is lacking in grapevine (Vitis vinifera L.). In this study, we performed a systematic analysis of the grape (V. vinifera) genome and reported that there are five SS genes (VvSS1–5) in the grape genome. Comparison of the structures of grape SS genes showed high structural conservation of grape SS genes, resulting from the selection pressures during the evolutionary process. The segmental duplication of grape SS genes contributed to this gene family expansion. The syntenic analyses between grape and soybean (Glycine max) demonstrated that these genes located in corresponding syntenic blocks arose before the divergence of grape and soybean. Phylogenetic analysis revealed distinct evolutionary paths for the grape SS genes. VvSS1/VvSS5, VvSS2/VvSS3 and VvSS4 originated from three ancient SS genes, which were generated by duplication events before the split of monocots and eudicots. Bioinformatics analysis of publicly available microarray data, which was validated by quantitative real-time reverse transcription PCR (qRT-PCR), revealed distinct temporal and spatial expression patterns of VvSS genes in various tissues, organs and developmental stages, as well as in response to biotic and abiotic stresses. Taken together, our results will be beneficial for further investigations into the functionsof SS gene in the processes of grape resistance to environmental stresses. Full article

Telomeres are essential chromosomal regions that prevent critical shortening of linear chromosomes and genomic instability in eukaryotic cells. The bulk of telomeric DNA is replicated by semi-conservative DNA replication in the same way as the rest of the genome. However, recent findings revealed that replication of telomeric repeats is a potential cause of chromosomal instability, because DNA replication through telomeres is challenged by the repetitive telomeric sequences and specific structures that hamper the replication fork. In this review, we summarize current understanding of the mechanisms by which telomeres are faithfully and safely replicated in mammalian cells. Various telomere-associated proteins ensure efficient telomere replication at different steps, such as licensing of replication origins, passage of replication forks, proper fork restart after replication stress, and dissolution of post-replicative structures. In particular, shelterin proteins have central roles in the control of telomere replication. Through physical interactions, accessory proteins are recruited to maintain telomere integrity during DNA replication. Dormant replication origins and/or homology-directed repair may rescue inappropriate fork stalling or collapse that can cause defects in telomere structure and functions. Full article

Duchenne muscular dystrophy (DMD) is caused by defects in the DMD gene and results in progressive wasting of skeletal and cardiac muscle due to an absence of functional dystrophin. Cardiomyopathy is prominent in DMD patients, and contributes significantly to mortality. This is particularly true following respiratory interventions that reduce death rate and increase ambulation and consequently cardiac load. Cardiomyopathy shows an increasing prevalence with age and disease progression, and over 95% of patients exhibit dilated cardiomyopathy by the time they reach adulthood. Development of the myopathy is complex, and elevations in intracellular calcium, functional muscle ischemia, and mitochondrial dysfunction characterise the pathophysiology. Current therapies are limited to treating symptoms of the disease and there is therefore an urgent need to treat the underlying genetic defect. Several novel therapies are outlined here, and the unprecedented success of phosphorodiamidate morpholino oligomers (PMOs) in preclinical and clinical studies is overviewed. Full article

The shiitake mushroom (Lentinulaedodes) is one of the most popular edible mushrooms in the world and has attracted attention for its value in medicinal and pharmacological uses. With recent advanced research and techniques, the agricultural cultivation of the shiitake mushroom has been greatly increased, especially in East Asia. Additionally, demand for the development of new cultivars with good agricultural traits has been greatly enhanced, but the development processes are complicated and more challenging than for other edible mushrooms. In this study, we developed 44 novel polymorphic simple sequence repeat (SSR) markers for the determination of shiitake mushroom cultivars based on a whole genome sequencing database of L. edodes. These markers were found to be polymorphic and reliable when screened in 23 shiitake mushroom cultivars. For the 44 SSR markers developed in this study, the major allele frequency ranged from 0.13 to 0.94; the number of genotypes and number of alleles were each 2–11; the observed and expected heterozygosity were 0.00–1.00 and 0.10–0.90, respectively; and the polymorphic information content value ranged from 0.10 to 0.89. These new markers can be used for molecular breeding, the determination of cultivars, and other applications. Full article

Brain tumors are the second most common group of childhood cancers, accounting for about 20%–25% of all pediatric tumors. Deregulated expression of the MYC family of transcription factors, particularly c-MYC and MYCN genes, has been found in many of these neoplasms, and their expression levels are often correlated with poor prognosis. Elevated c-MYC/MYCN initiates and drives tumorigenesis in many in vivo model systems of pediatric brain tumors. Therefore, inhibition of their oncogenic function is an attractive therapeutic target. In this review, we explore the roles of MYC oncoproteins and their molecular targets during the formation, maintenance, and recurrence of childhood brain tumors. We also briefly summarize recent progress in the development of therapeutic approaches for pharmacological inhibition of MYC activity in these tumors. Full article

Smokeless tobacco (ST) products vary significantly in their oral carcinogenicity. Much is known about the differences in the chemical, but not the bacterial, constituents of these products. In this study, we explored the composition and function of the bacteriome in ST products from four countries using quantitative polymerase chain reaction (qPCR) and 16S rRNA-based next generation sequencing. The bacterial load (16S rRNA copies/gram) was lowest in Swedish snus (3.4 × 10⁶) and highest in Yemeni shammah (6.6 × 10¹¹). A total of 491 species-level taxa, many of which are potentially novel, belonging to 178 genera and 11 phyla were identified. Species richness and diversity were highest for Swedish snus and lowest for Yemeni shammah. Bacillus, Paenibacillus, and Oceanobacillus spp. were the most abundant in American snuff; species of Pseudomonas, Massilia, Propionibacterium, Puniceispirillum, and Gloeothece predominated in Swedish snus. In Sudanese toombak, Facklamia, Desemzia, Atopostipes, and Lysinibacillus spp. accounted for the majority of the bacteriome. Yemeni shammah exclusively contained Bacillus spp. Functional prediction by phylogenetic investigation of communities by reconstruction of unobserved states (PICRUSt) showed that genes encoding cadmium/zinc and nickel transport systems were enriched in the presumptively “high carcinogenicity” products. The bacteriome of ST products thus differed qualitatively, quantitatively, and functionally. The relevance of these differences, particularly with respect to nickel and cadmium, to oral carcinogenesis warrants further investigation. Full article

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.
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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

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

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

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

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

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

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

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

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