The recent release of the domestic dog genome provides us with an ideal opportunity to investigate dog-specific genomic features. In this study, we performed a systematic analysis of CpG islands (CGIs), which are often considered gene markers, in the dog genome. Relative to the human and mouse genomes, the dog genome has a remarkably large number of CGIs and high CGI density, which is contributed by its noncoding sequences. Surprisingly, the dog genome has fewer CGIs associated with the promoter regions of genes than the human or the mouse. Further examination of functional features of dog-human-mouse homologous genes suggests that the dog might have undergone a faster erosion rate of promoter-associated CGIs than the human or mouse. Some genetic or genomic factors such as local recombination rate and karyotype may be related to the unique dog CGI features.

Myocardial infarction (MI) is a leading cause of death in the world and many genes are involved in it. Transcription factor (TFs) and microRNAs (miRNAs) are key regulators of gene expression. We hypothesized that miRNAs and TFs might play combinatory regulatory roles in MI. After collecting MI candidate genes and miRNAs from various resources, we constructed a comprehensive MI-specific miRNA-TF co-regulatory network by integrating predicted and experimentally validated TF and miRNA targets. We found some hub nodes (e.g. miR-16 and miR-26) in this network are important regulators, and the network can be severed as a bridge to interpret the associations of previous results, which is shown by the case of miR-29 in this study. We also constructed a regulatory network for MI recurrence and found several important genes (e.g. DAB2, BMP6, miR-320 and miR-103), the abnormal expressions of which may be potential regulatory mechanisms and markers of MI recurrence. At last we proposed a cellular model to discuss major TF and miRNA regulators with signaling pathways in MI. This study provides more details on gene expression regulation and regulators involved in MI progression and recurrence. It also linked up and interpreted many previous results.

The plastids and mitochondria of the eukaryotic cell are of endosymbiotic origin. These events occurred ~2 billion years ago and produced significant changes in the genomes of the host and the endosymbiont. Previous studies demonstrated that the invasion of land affected plastids and mitochondria differently and that the paths of mitochondrial integration differed between animals and plants. Other studies examined the reasons why a set of proteins remained encoded in the organelles and were not transferred to the nuclear genome. However, our understanding of the functional relations of the transferred genes is insufficient. In this paper, we report a high-throughput phylogenetic analysis to identify genes of cyanobacterial origin for plants of different levels of complexity: Arabidopsis thaliana, Chlamydomonas reinhardtii, Physcomitrella patens, Populus trichocarpa, Selaginella moellendorffii, Sorghum bicolor, Oryza sativa, and Ostreococcus tauri. Thus, a census of cyanobacterial gene recruits and a study of their function are presented to better understand the functional aspects of plastid symbiogenesis. From algae to angiosperms, the GO terms demonstrated a gradual expansion over functionally related genes in the nuclear genome, beginning with genes related to thylakoids and photosynthesis, followed by genes involved in metabolism, and finally with regulation-related genes, primarily in angiosperms. The results demonstrate that DNA is supplied to the nuclear genome on a permanent basis with no regard to function, and only what is needed is kept, which thereby expands on the GO space along the related genes.

Long non-coding RNAs (lncRNAs) play key roles in various cellular contexts and diseases by diverse mechanisms. With the rapid growth of identified lncRNAs and disease-associated single nucleotide polymorphisms (SNPs), there is a great demand to study SNPs in lncRNAs. Aiming to provide a useful resource about lncRNA SNPs, we systematically identified SNPs in lncRNAs and analyzed their potential impacts on lncRNA structure and function. In total, we identified 495,729 and 777,095 SNPs in more than 30,000 lncRNA transcripts in human and mouse, respectively. A large number of SNPs were predicted with the potential to impact on the miRNA-lncRNA interaction. The experimental evidence and conservation of miRNA-lncRNA interaction, as well as miRNA expressions from TCGA were also integrated to prioritize the miRNA-lncRNA interactions and SNPs on the binding sites. Furthermore, by mapping SNPs to GWAS results, we found that 142 human lncRNA SNPs are GWAS tagSNPs and 197,827 lncRNA SNPs are in the GWAS linkage disequilibrium regions. All these data for human and mouse lncRNAs were imported into lncRNASNP database (http://bioinfo.life.hust.edu.cn/lncRNASNP/), which includes two sub-databases lncRNASNP-human and lncRNASNP-mouse. The lncRNASNP database has a user-friendly interface for searching and browsing through the SNP, lncRNA and miRNA sections.

Transcription factors (TFs) are proteins that bind to specific DNA sequences, thereby playing crucial roles in gene-expression regulation through controlling the transcription of genetic information from DNA to RNA. Transcription cofactors and chromatin remodeling factors are also essential in the gene transcriptional regulation. Identifying and annotating all the TFs are primary and crucial steps for illustrating their functions and understanding the transcriptional regulation. In this study, based on manual literature reviews, we collected and curated 72 TF families for animals, which is currently the most complete list of TF families in animals. Then, we systematically characterized all the TFs in 50 animal species and constructed a comprehensive animal TF database, AnimalTFDB. To better serve the community, we provided detailed annotations for each TF, including basic information, gene structure, functional domain, 3D structure hit, Gene Ontology, pathway, protein-protein interaction, paralogs, orthologs, potential TF-binding sites and targets. In addition, we collected and annotated transcription cofactors and chromatin remodeling factors. AnimalTFDB has a user-friendly web interface with multiple browse and search functions, as well as data downloading. It is freely available at http://www.bioguo.org/AnimalTFDB/.

Although long non-coding RNAs (lncRNAs) predominately reside in the nucleus and exert their functions in many biological processes, their potential involvement in cytoplasmic signal transduction remains unexplored. Here, we identify a cytoplasmic lncRNA, LINK-A (long intergenic non-coding RNA for kinase activation), which mediates HB-EGF-triggered, EGFR:GPNMB heterodimer-dependent HIF1α phosphorylation at Tyr 565 and Ser 797 by BRK and LRRK2, respectively. These events cause HIF1α stabilization, HIF1α-p300 interaction, and activation of HIF1α transcriptional programs under normoxic conditions. Mechanistically, LINK-A facilitates the recruitment of BRK to the EGFR:GPNMB complex and BRK kinase activation. The BRK-dependent HIF1α Tyr 565 phosphorylation interferes with Pro 564 hydroxylation, leading to normoxic HIF1α stabilization. Both LINK-A expression and LINK-A-dependent signalling pathway activation correlate with triple-negative breast cancer (TNBC), promoting breast cancer glycolysis reprogramming and tumorigenesis. Our findings illustrate the magnitude and diversity of cytoplasmic lncRNAs in signal transduction and highlight the important roles of lncRNAs in cancer.

Transcribed-ultraconserved regions (T-UCRs) are long non-coding RNAs (lncRNA) encoded by a subset of long ultraconserved stretches in the human genome. Recent studies revealed that the expression of several T-UCRs is altered in cancer and growing evidences underline the importance of T-UCRs in oncogenesis, offering also potential new strategies for diagnosis and prognosis. We found that overexpression of one specific T-UCRs named uc.63 is associated with bad outcome in luminal A subtype of breast cancer patients. uc.63 is localized in the third intron of exportin-1 gene (XPO1) and is transcribed in the same orientation of its host gene. Interestingly, silencing of uc.63 induces apoptosis in vitro. However, silencing of host gene XPO1 does not cause the same effect suggesting that the transcription of uc.63 is independent of XPO1. Our results reveal an important role of uc.63 in promoting breast cancer cells survival and offer the prospect to identify a signature associated with poor prognosis.

The Macleaya spp., including Macleaya cordata and Macleaya microcarpa, are traditional anti-virus, inflammation eliminating, and insecticide herb medicines for their isoquinoline alkaloids. They are also known as the basis of the popular natural animal food addictive in Europe. However, few studies especially at genomics level were conducted on them. Hence, we performed the Macleaya spp. transcriptome and integrated it with iTRAQ proteome analysis in order to identify potential genes involved in alkaloids biosynthesis.

Familial hypertrophic cardiomyopathy (HCM) is a prevalent hereditary cardiac disorder linked to arrhythmia and sudden cardiac death. While the causes of HCM have been identified as genetic mutations in the cardiac sarcomere, the pathways by which sarcomeric mutations engender myocyte hypertrophy and electrophysiological abnormalities are not understood. To elucidate the mechanisms underlying HCM development, we generated patient-specific induced pluripotent stem cell cardiomyocytes (iPSC-CMs) from a ten-member family cohort carrying a hereditary HCM missense mutation (Arg663His) in the MYH7 gene. Diseased iPSC-CMs recapitulated numerous aspects of the HCM phenotype including cellular enlargement and contractile arrhythmia at the single-cell level. Calcium (Ca(2+)) imaging indicated dysregulation of Ca(2+) cycling and elevation in intracellular Ca(2+) ([Ca(2+)](i)) are central mechanisms for disease pathogenesis. Pharmacological restoration of Ca(2+) homeostasis prevented development of hypertrophy and electrophysiological irregularities. We anticipate that these findings will help elucidate the mechanisms underlying HCM development and identify novel therapies for the disease.

There has been much interest in CpG islands (CGIs), clusters of CpG dinucleotides in GC-rich regions, because they are considered gene markers and involved in gene regulation. To date, there has been no genome-wide analysis of CGIs in the fish genome. We first evaluated the performance of three popular CGI identification algorithms in four fish genomes (tetraodon, stickleback, medaka, and zebrafish). Our results suggest that Takai and Jones' (2002) algorithm is most suitable for comparative analysis of CGIs in the fish genome. Then, we performed a systematic analysis of CGIs in the four fish genomes using Takai and Jones' algorithm, compared to other vertebrate genomes. We found that both the number of CGIs and the CGI density vary greatly among these genomes. Remarkably, each fish genome presents a distinct distribution of CGI density with some genomic factors (e.g., chromosome size and chromosome GC content). These findings are helpful for understanding evolution of fish genomes and the features of fish CGIs.

Cancer genes tend to be highly mutated under positive selection. Better understanding the recurrently mutated genes (RMGs) in cancer is critical for explicating the mechanisms of tumorigenesis and providing vital clues for therapy. Although some studies have investigated functional impacts of RMGs in specific cancer types, a comprehensive analysis of RMGs and their mutational impacts across cancers is still needed.

The protein translational system, including transfer RNAs (tRNAs) and several categories of enzymes, plays a key role in regulating cell proliferation. Translation dysregulation also contributes to cancer development, though relatively little is known about the changes that occur to the translational system in cancer. Here, we present global analyses of tRNAs and three categories of enzymes involved in translational regulation in ~10,000 cancer patients across 31 cancer types from The Cancer Genome Atlas. By analyzing the expression levels of tRNAs at the gene, codon, and amino acid levels, we identified unequal alterations in tRNA expression, likely due to the uneven distribution of tRNAs decoding different codons. We find that overexpression of tRNAs recognizing codons with a low observed-over-expected ratio may overcome the translational bottleneck in tumorigenesis. We further observed overall overexpression and amplification of tRNA modification enzymes, aminoacyl-tRNA synthetases, and translation factors, which may play synergistic roles with overexpression of tRNAs to activate the translational systems across multiple cancer types.

Renal impairment (RI) is one of the hallmarks of multiple myeloma (MM) and carries a poor prognosis. Microvesicles (MVs) are membrane vesicles and play an important role in disease progression. Here, we investigated the role of MVs derived from MM cells (MM-MVs) in RI of MM. We found that MM-MVs significantly inhibited viability and induced apoptosis, but not epithelial-mesenchymal transition in human kidney-2 (HK-2), a human renal tubular epithelial cell line. The protein levels of cleaved caspase-3, 8, and 9, and E-cadherin, were increased, but vementin levels were decreased in the HK-2 cells treated with MM-MVs. Through a comparative sequencing and analysis of RNA content between the MVs from RPMI8226 MM cells (RPMI8226-MVs) and K562 leukemia cells, RPMI8226-MVs were enriched with more renal-pathogenic miRNAs, in which the selective miRNAs may participate in the up-regulation of the levels of cleaved caspase-3. Furthermore, the levels of CD138+ circulating MVs (cirMVs) in the peripheral blood were positively correlated with the severity of RI in newly-diagnosed MM. Our study supports MM-MVs representing a previously undescribed factor and playing a potential role in the development of RI of MM patients, and sheds light on the potential application of CD138+ cirMV counts in precise diagnosis of RI in MM and exploring MM-MVs as a therapeutic target.

Half of the chronic myeloid leukemia (CML) patients with sustained deep molecular response suffer from relapse after discontinuation mainly because tyrosine kinase inhibitors (TKIs) cannot eradicate leukemia stem cells (LSCs). In addition, tumor necrosis factor α (TNF-α) is highly detected in CML patients. Our aim was to explore whether TNF-α is a potential target for LSC elimination.

Perna viridis and P. canaliculus are economically and ecologically important species of shellfish. In this study, the complete ribosomal DNA (rDNA) unit sequences of these species were determined for the first time. The gene order, 18S rRNA-internal transcribed spacer (ITS) 1-5.8S rRNA-ITS2-28S rRNA-intergenic spacer (IGS), was similar to that observed in other eukaryotes. The lengths of the P. viridis and P. canaliculus rDNA sequences ranged from 8,432 to 8,616 bp and from 7,597 to 7,610 bp, respectively, this variability was mainly attributable to the IGS region. The putative transcription termination site and initiation site were confirmed. Perna viridis and P. canaliculus rDNA contained two (length: 93 and 40 bp) and one (length: 131 bp) repeat motifs, respectively. Individual intra-species differences mainly involved the copy number of repeat units. In P. viridis, three cytosine-guanine (CpG) sites with sizes of 440, 1,075 and 537 bp were found to cover nearly the entire IGS sequence, whereas in P. canaliculus, two CpG islands with sizes of 361 and 484 bp were identified. The phylogenetic trees constructed with maximum likelihood and neighbour-joining methods and based on ITS sequences were identical and included three major clusters. Species of the same genus were easily clustered together.

The goal of this study was to prepare lyophilized platelet-rich fibrin (L-PRF) and analyze the combined use of L-PRF and osteogenic bone marrow mesenchymal stem cell (BMSC) sheet fragments for bone tissue engineering via in vivo injection.

Cardiac differentiation from human pluripotent stem cells provides a unique opportunity to study human heart development in vitro and offers a potential cell source for cardiac regeneration. Compared to the large body of studies investigating cardiac maturation and cardiomyocyte subtype-specific induction, molecular events underlying cardiac lineage commitment from pluripotent stem cells at early stage remain poorly characterized.

Circular RNA (circRNA) is a large group of RNA family extensively existed in cells and tissues. High-throughput sequencing provides a way to view circRNAs across different samples, especially in various diseases. However, there is still no comprehensive database for exploring the cancer-specific circRNAs. We collected 228 total RNA or polyA(-) RNA-seq samples from both cancer and normal cell lines, and identified 272 152 cancer-specific circRNAs. A total of 950 962 circRNAs were identified in normal samples only, and 170 909 circRNAs were identified in both tumor and normal samples, which could be further used as non-tumor background. We constructed a cancer-specific circRNA database (CSCD, http://gb.whu.edu.cn/CSCD). To understand the functional effects of circRNAs, we predicted the microRNA response element sites and RNA binding protein sites for each circRNA. We further predicted potential open reading frames to highlight translatable circRNAs. To understand the association between the linear splicing and the back-splicing, we also predicted the splicing events in linear transcripts of each circRNA. As the first comprehensive cancer-specific circRNA database, we believe CSCD could significantly contribute to the research for the function and regulation of cancer-associated circRNAs.

Faster acclimatization to high altitude upon re-ascent is seen in humans; however, the molecular basis for this enhanced adaptive response is unknown. We report that in healthy lowlanders, plasma adenosine levels are rapidly induced by initial ascent to high altitude and achieved even higher levels upon re-ascent, a feature that is positively associated with quicker acclimatization. Erythrocyte equilibrative nucleoside transporter 1 (eENT1) levels are reduced in humans at high altitude and in mice under hypoxia. eENT1 deletion allows rapid accumulation of plasma adenosine to counteract hypoxic tissue damage in mice. Adenosine signalling via erythrocyte ADORA2B induces PKA phosphorylation, ubiquitination and proteasomal degradation of eENT1. Reduced eENT1 resulting from initial hypoxia is maintained upon re-ascent in humans or re-exposure to hypoxia in mice and accounts for erythrocyte hypoxic memory and faster acclimatization. Our findings suggest that targeting identified purinergic-signalling network would enhance the hypoxia adenosine response to counteract hypoxia-induced maladaptation.

T cells and the T-cell receptor (TCR) repertoire play pivotal roles in immune response and immunotherapy. TCR sequencing (TCR-Seq) technology has enabled accurate profiling TCR repertoire and currently a large number of TCR-Seq data are available in public. Based on the urgent need to effectively re-use these data, we developed TCRdb, a comprehensive human TCR sequences database, by a uniform pipeline to characterize TCR sequences on TCR-Seq data. TCRdb contains more than 277 million highly reliable TCR sequences from over 8265 TCR-Seq samples across hundreds of tissues/clinical conditions/cell types. The unique features of TCRdb include: (i) comprehensive and reliable sequences for TCR repertoire in different samples generated by a strict and uniform pipeline of TCRdb; (ii) powerful search function, allowing users to identify their interested TCR sequences in different conditions; (iii) categorized sample metadata, enabling comparison of TCRs in different sample types; (iv) interactive data visualization charts, describing the TCR repertoire in TCR diversity, length distribution and V-J gene utilization. The TCRdb database is freely available at http://bioinfo.life.hust.edu.cn/TCRdb/ and will be a useful resource in the research and application community of T cell immunology.