TDP-43 regulates cancer-associated microRNAs

Aberrant regulation of miRNA genes contributes to pathogenesis of a wide range of human diseases, including cancer. The TAR DNA binding protein 43 (TDP-43), a RNA/DNA binding protein associated with neurodegeneration, is involved in miRNA biogenesis. Here, we systematically examined miRNAs regulated by TDP-43 using RNA-Seq coupled with an siRNA-mediated knockdown approach. TDP-43 knockdown affected the expression of a number of miRNAs. In addition, TDP-43 down-regulation led to alterations in the patterns of different isoforms of miRNAs (isomiRs) and miRNA arm selection, suggesting a previously unknown role of TDP-43 in miRNA processing. A number of TDP-43 associated miRNAs, and their candidate target genes, are associated with human cancers. Our data reveal highly complex roles of TDP-43 in regulating different miRNAs and their target genes. Our results suggest that TDP-43 may promote migration of lung cancer cells by regulating miR-423-3p. In contrast, TDP-43 increases miR-500a-3p expression and binds to the mature miR-500a-3p sequence. Reduced expression of miR-500a-3p is associated with poor survival of lung cancer patients, suggesting that TDP-43 may have a suppressive role in cancer by regulating miR-500a-3p. Cancer-associated genes LIF and PAPPA are possible targets of miR-500a-3p. Our work suggests that TDP-43-regulated miRNAs may play multifaceted roles in the pathogenesis of cancer.

Analysis of the p53/CEP-1 regulated non-coding transcriptome in C. elegans by an NSR-seq strategy

In recent years, large numbers of non-coding RNAs (ncRNAs) have been identified in C. elegans but their functions are still not well studied. In C. elegans, CEP-1 is the sole homolog of the p53 family of genes. In order to obtain transcription profiles of ncRNAs regulated by CEP-1 under normal and UV stressed conditions, we applied the 'not-so-random' hexamers priming strategy to RNA sequencing in C. elegans, This NSR-seq strategy efficiently depleted rRNA transcripts from the samples and showed high technical replicability. We identified more than 1,000 ncRNAs whose apparent expression was repressed by CEP-1, while around 200 were activated. Around 40% of the CEP-1 activated ncRNAs promoters contain a putative CEP-1-binding site. CEP-1 regulated ncRNAs were frequently clustered and concentrated on the X chromosome. These results indicate that numerous ncRNAs are involved in CEP-1 transcriptional network and that these are especially enriched on the X chromosome in C. elegans.

CloudLCA: finding the lowest common ancestor in metagenome analysis using cloud computing

Estimating taxonomic content constitutes a key problem in metagenomic sequencing data analysis. However, extracting such content from high-throughput data of next-generation sequencing is very time-consuming with the currently available software. Here, we present CloudLCA, a parallel LCA algorithm that significantly improves the efficiency of determining taxonomic composition in metagenomic data analysis. Results show that CloudLCA (1) has a running time nearly linear with the increase of dataset magnitude, (2) displays linear speedup as the number of processors grows, especially for large datasets, and (3) reaches a speed of nearly 215 million reads each minute on a cluster with ten thin nodes. In comparison with MEGAN, a well-known metagenome analyzer, the speed of CloudLCA is up to 5 more times faster, and its peak memory usage is approximately 18.5% that of MEGAN, running on a fat node. CloudLCA can be run on one multiprocessor node or a cluster. It is expected to be part of MEGAN to accelerate analyzing reads, with the same output generated as MEGAN, which can be import into MEGAN in a direct way to finish the following analysis. Moreover, CloudLCA is a universal solution for finding the lowest common ancestor, and it can be applied in other fields requiring an LCA algorithm.

Combined Action of ACE Gene I/D and GNB3 Gene C825T Polymorphisms on Essential Hypertension in Northern Han Chinese / 生物化学与生物物理进展

Essential hypertension (EH), a complex polygenic disease, is considered to the result of the genetic interaction of multiple gene alterations in concert with environmental factors. Evidences showed that angiotensin-converting enzyme (ACE) gene and G protein beta3 subunit (GNB3) gene are both important susceptibility genes for EH, and that there exists putative biological connection between the two genes in developing hypertension. To investigate whether hypertension was affected by gene-gene interaction between the two genes in the northern Chinese Han population, a case-control association study including 502 hypertensive cases and 490healthy controls was conducted, selecting the ACE gene I/D polymorpinsm and the GNB3 gene C825T polymorphism. Linkage disequilibrium analysis revealed a significant nonrandom distribution only in male hypertensives, indicating that interaction between ACE gene and GNB3 gene may predispose males to the occurrence of hypertension. Multivariate stepwise logistic regression in single locus analysis, with adjustment for common risk factors for hypertension, demonstrated that the OR for DD/ID versus Ⅱ for hypertension among men was significant (OR 1.57; 95% CI, 1.09 ～2.27; P = 0.016) in dominant genetic model. In combination analysis stratified with respect to gender, slightly significant ORs were found after adjustment in males: OR for TT vs CC, 0.11; 95%CI, 0.01 ～0.99; P = 0.049 within ACE DD genotype; OR for DD/ID vs Ⅱ, 1.52; 95% CI, 1.01 ～2.29; P = 0.047 within GNB3 CC+CT genotype. The results suggest that ACE, or a nearby gene, is a male-specific susceptible gene for hypertension, and that there may exist epistatic gene-gene interaction between ACE D allele and GNB3 825C allele.

Comparison of Properties of Tumor Necrosis Factor-α Converting Enzyme (TACE) and Some Matrix Metalloproteases (MMPs) in Catalytic Domains / 华中科技大学学报（医学）（英德文版）

The crystal structural data of TACE, MMP-1, MMP-2, MMP-3 and MMP-9 were obtained from PDB database, and then their catalytic domains' properties including conformation, molecular surface hydrophobicity and electrostatic potential were analyzed and compared by using Insight Ⅱ molecular modeling software. It was found that the conformation and molecular surface hydrophobicity of catalytic domains of TACE and MMPs were not obviously different, but the molecular surface electrostatic potential of catalytic domain of TACE and MMPs had obvious differences.The findings are helpful in the Rational Drug Design of TACE selective inhibitor.

The Discovery and Progress of RNA Interference:a Brief Introduction to The Nobel Prize in Physiology or Medicine 2006 / 生物化学与生物物理进展

RNA interference is a very important mechanism for the regulation of gene expression, participates in defense against viral infections, and keeps jumping genes under control. RNA interference has been taken as a powerful "gene silence" method widely used in basic science to study the function of genes, and it may lead to novel therapies in the future.

Comparison of properties of tumor necrosis factor-alpha converting enzyme (TACE) and some matrix metalloproteases (MMPs) in catalytic domains / 华中科技大学学报（医学）（英德文版）

The crystal structural data of TACE, MMP-1, MMP-2, MMP-3 and MMP-9 were obtained from PDB database, and then their catalytic domains' properties including conformation, molecular surface hydrophobicity and electrostatic potential were analyzed and compared by using Insight II molecular modeling software. It was found that the conformation and molecular surface hydrophobicity of catalytic domains of TACE and MMPs were not obviously different, but the molecular surface electrostatic potential of catalytic domain of TACE and MMPs had obvious differences. The findings are helpful in the Rational Drug Design of TACE selective inhibitor.