To survey hepatitis B virus (HBV) integration in liver cancer genomes, we conducted massively parallel sequencing of 81 HBV-positive and 7 HBV-negative hepatocellular carcinomas (HCCs) and adjacent normal tissues. We found that HBV integration is observed more frequently in the tumors (86.4%) than in adjacent liver tissues (30.7%). Copy-number variations (CNVs) were significantly increased at HBV breakpoint locations where chromosomal instability was likely induced. Approximately 40% of HBV breakpoints within the HBV genome were located within a 1,800-bp region where the viral enhancer, X gene and core gene are located. We also identified recurrent HBV integration events (in ≥ 4 HCCs) that were validated by RNA sequencing (RNA-seq) and Sanger sequencing at the known and putative cancer-related TERT, MLL4 and CCNE1 genes, which showed upregulated gene expression in tumor versus normal tissue. We also report evidence that suggests that the number of HBV integrations is associated with patient survival.
Using next-generation sequencing technology alone, we have successfully generated and assembled a draft sequence of the giant panda genome. The assembled contigs (2.25 gigabases (Gb)) cover approximately 94% of the whole genome, and the remaining gaps (0.05 Gb) seem to contain carnivore-specific repeats and tandem repeats. Comparisons with the dog and human showed that the panda genome has a lower divergence rate. The assessment of panda genes potentially underlying some of its unique traits indicated that its bamboo diet might be more dependent on its gut microbiome than its own genetic composition. We also identified more than 2.7 million heterozygous single nucleotide polymorphisms in the diploid genome. Our data and analyses provide a foundation for promoting mammalian genetic research, and demonstrate the feasibility for using next-generation sequencing technologies for accurate, cost-effective and rapid de novo assembly of large eukaryotic genomes.
Here we present the first diploid genome sequence of an Asian individual. The genome was sequenced to 36-fold average coverage using massively parallel sequencing technology. We aligned the short reads onto the NCBI human reference genome to 99.97% coverage, and guided by the reference genome, we used uniquely mapped reads to assemble a high-quality consensus sequence for 92% of the Asian individual's genome. We identified approximately 3 million single-nucleotide polymorphisms (SNPs) inside this region, of which 13.6% were not in the dbSNP database. Genotyping analysis showed that SNP identification had high accuracy and consistency, indicating the high sequence quality of this assembly. We also carried out heterozygote phasing and haplotype prediction against HapMap CHB and JPT haplotypes (Chinese and Japanese, respectively), sequence comparison with the two available individual genomes (J. D. Watson and J. C. Venter), and structural variation identification. These variations were considered for their potential biological impact. Our sequence data and analyses demonstrate the potential usefulness of next-generation sequencing technologies for personal genomics.
Arginine methylation governs important cellular processes that impact growth and proliferation, as well as differentiation and development. Through their ability to catalyze symmetric or asymmetric methylation of histones and non-histone proteins, members of the protein arginine methyltransferase (PRMT) family regulate chromatin structure and expression of a wide spectrum of target genes. Unlike other PRMTs, PRMT5 works in concert with a variety of cellular proteins including ATP-dependent chromatin remodelers and co-repressors to induce epigenetic silencing. Recent work also implicates PRMT5 in the control of growth-promoting and pro-survival pathways, demonstrating its versatility as an enzyme involved in both epigenetic regulation of anti-cancer target genes and organelle biogenesis. These studies not only provide insight into the molecular mechanisms by which PRMT5 contributes to growth control, but also justify targeting PRMT5 therapeutically.
Background: PRMT7 symmetrically methylates histones H2A and H4, and modulates cellular response to DNA damage. Results: PRMT7 interacts with BRG1-hSWI/SNF, targets H2AR3 and H4R3, and represses expression of POLD1. Conclusion: PRMT7 regulates response to DNA damage and confers resistance to DNA-damaging agents. Significance: Understanding how PRMT7 regulates response to genotoxic stress will clarify how cancer cells become drug-resistant.
The incorporation of nanoparticles into thermosetting resins is seen to impart desirable dielectric properties when compared with conventional (micron-sized particulates) composites. Although the improvements are accompanied by the mitigation of internal charge in the materials, the nature of the interfacial region is shown to be pivotal in determining the dielectric behaviour. In particular, it is shown that the conditions and enhanced area of the interface changes the bonding that may give rise to an interaction zone, which affects the interfacial polarization through the formation of local conductivity.
Sonodynamic therapy (SDT) always causes tumor hypoxia aggravation which can induce malignant cell proliferation and drug resistance. To overcome these disadvantages, a cascaded drug delivery system (Lipo/HMME/ACF@MnO2‐AS1411) is constructed for synergistic enhanced sonodynamic therapy. First, hematoporphyrin monomethyl ether (HMME) and acriflavine (ACF) are encapsulated in the lipid layers and the inner aqueous cores of the liposomes, respectively. Then the ultrathin manganese dioxide (MnO2) nanosheets are coated on the surface of the liposomes by using KMnO4 and polyethylene glycol through “one step reduction and modification” method. Furthermore, the nanoparticles are decorated with tumor‐targeting AS1411 aptamer through the phosphate groups on the DNA strand which can bind to Mn sites to obtain Lipo/HMME/ACF@MnO2‐AS1411 delivery system. Herein, HMME can act as a sonosensitizer, and ACF is used to prevent the formation of HIF‐1α/HIF‐1β dimerization to overcome the negative effects after SDT. The Lipo/HMME/ACF@MnO2‐AS1411 delivery system has multiple functions, including codelivery of HMME and ACF, pH/glutathione/ultrasound triple responses, synergistic cascaded enhancement of SDT, precise tumor‐targeting, and magnetic resonance imaging. The in vitro and in vivo results suggest that the Lipo/HMME/ACF@MnO2‐AS1411 delivery system is a promising core–shell nanoplatform for synergistic enhancement of sonodynamic therapy, which can provide a new approach in the related research fields.
Regulation of adipose tissue formation by adipogenic-regulatory proteins has long been a topic of interest given the ever-increasing health concerns of obesity and type 2 diabetes in the general population. Differentiation of precursor cells into adipocytes involves a complex network of cofactors that facilitate the functions of transcriptional regulators from the CCATT/enhancer binding protein, and the peroxisome proliferator-activated receptor (PPAR) families. Many of these cofactors are enzymes that modulate the structure of chromatin by altering histone-DNA contacts in an ATP-dependent manner or by posttranslationally modifying the histone proteins. Here we report that inhibition of protein arginine methyltransferase 5 (Prmt5) expression in multiple cell culture models for adipogenesis prevented the activation of adipogenic genes. In contrast, overexpression of Prmt5 enhanced adipogenic gene expression and differentiation. Chromatin immunoprecipitation experiments indicated that Prmt5 binds to and dimethylates histones at adipogenic promoters. Furthermore, the presence of Prmt5 promoted the binding of ATP-dependent chromatin-remodeling enzymes and was required for the binding of PPARγ2 at PPARγ2-regulated promoters. The data indicate that Prmt5 acts as a coactivator for the activation of adipogenic gene expression and promotes adipogenic differentiation.
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