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1. chinaXiv:201605.01731 [pdf]

GADD45A inhibits autophagy by regulating the interaction between BECN1 and PIK3C3

Zhang, Dongdong; Zhang, Weimin; Li, Dan; Fu, Ming; Zhan, Qimin; Zhang, Dongdong; Zhang, Weimin; Li, Dan; Fu, Ming; Zhan, Qimin; Zhang, Dongdong; Chen, Runsheng; Zhan, Qimin
分类: 生物学 >> 生物物理学 >> 细胞生物学

GADD45A is a TP53-regulated and DNA damage-inducible tumor suppressor protein, which regulates cell cycle arrest, apoptosis, and DNA repair, and inhibits tumor growth and angiogenesis. However, the function of GADD45A in autophagy remains unknown. In this report, we demonstrate that GADD45A plays an important role in regulating the process of autophagy. GADD45A is able to decrease LC3-II expression and numbers of autophagosomes in mouse tissues and different cancer cell lines. Using bafilomycin A(1) treatment, we have observed that GADD45A regulates autophagosome initiation. Likely, GADD45A inhibition of autophagy is through its influence on the interaction between BECN1 and PIK3C3. Immunoprecipitation and GST affinity isolation assays exhibit that GADD45A directly interacts with BECN1, and in turn dissociates the BECN1-PIK3C3 complex. Furthermore, we have mapped the 71 to 81 amino acids of the GADD45A protein that are necessary for the GADD45A interaction with BECN1. Knockdown of BECN1 can abolish autophagy alterations induced by GADD45A. Taken together, these findings provide the novel evidence that GADD45A inhibits autophagy via impairing the BECN1-PIK3C3 complex formation.

提交时间: 2016-05-15 点击量762下载量476 评论 0

2. chinaXiv:201605.01728 [pdf]

Association of echocardiographic left ventricular structure and-344C/T aldosterone synthase gene variant: A meta-analysis

Wang, Lijuan; Zhang, Bei; Wang, Hao; Li, Mei; Niu, Qiuli; Wen, Shaojun; Wang, Lijuan; Zhang, Bei; Wang, Hao; Li, Mei; Niu, Qiuli; Wen, Shaojun; Zhou, Jiapeng; Chen, Yubao; Zhou, Jiapeng; Chen, Runsheng
分类: 生物学 >> 生物物理学

Background: Aldosterone synthase (CYP11B2) is one of the most studied candidate genes related to essential hypertension (EH) and left ventricular hypertrophy (LVH). Some studies have focused on the relationship between -344C/T polymorphism (rs1799998) in the CYP11B2 gene and LVH, but the results are controversial. This meta-analysis is purposed to reveal the relationship between the -344C/T and the left ventricular structure and function, including left ventricular end diastolic dimension (LVEDD), left ventricular end systolic diameter (LVESD), left ventricular mass/left ventricular mass index (LVM/LVMI), left ventricular posterior wall thickness (LVPWT), and interventricular septal wall thickness (IVS). Methods: A literature search of PubMed and Embase databases was conducted on articles published before January 27, 2014. The odds ratios with 95% confidence intervals were calculated. Heterogeneity analyses were performed using meta-regression. Tests for publication bias were also performed and biased studies should be removed from subsequent analyses. Results: There were 20 studies with a total of 6780 subjects meeting the inclusion criteria. The main finding was that concentration levels of LVEDD and LVESD were higher in CC homozygous individuals than in TT homozygous individuals in the whole group. In the Asian subgroup, TT homozygous individuals had larger IVS than CC homozygous individuals. In the Caucasian normotension subgroup, CC homozygous individuals had larger LVM/LVMI than TT homozygous individuals. In the Asian essential hypertension subgroup, TT homozygous individuals had larger LVPWT values than CC homozygous individuals. Conclusions: The present findings support the hypothesis that CC homozygous individuals may have greater left ventricular diameters (LVEDD and LVESD) regardless of their ethnicities or physical conditions.

提交时间: 2016-05-15 点击量578下载量176 评论 0

3. chinaXiv:201605.01489 [pdf]

MIWI and piRNA-mediated cleavage of messenger RNAs in mouse testes

Zhang, Peng; Wang, Jiajia; Huang, Da-Wei; He, Shunmin; Kang, Jun-Yan; Gou, Lan-Tao; Dai, Peng; Liu, Mo-Fang; Kang, Jun-Yan; Gou, Lan-Tao; Dai, Peng; Liu, Mo-Fang; Skogerboe, Geir; Chen, Runsheng; Xue, Yuanchao; Fu, Xiang-Dong; Xue, Yuanchao; Fu, Xiang-Dong
分类: 生物学 >> 生物物理学 >> 细胞生物学

The piRNA machinery is known for its role in mediating epigenetic silencing of transposons. Recent studies suggest that this function also involves piRNA-guided cleavage of transposon-derived transcripts. As many piRNAs also appear to have the capacity to target diverse mRNAs, this raises the intriguing possibility that piRNAs may act extensively as siRNAs to degrade specific mRNAs. To directly test this hypothesis, we compared mouse PIWI (MIWI)-associated piRNAs with experimentally identified cleaved mRNA fragments from mouse testes, and observed cleavage sites that predominantly occur at position 10 from the 5' end of putative targeting piRNAs. We also noted strong biases for U and A residues at nucleotide positions 1 and 10, respectively, in both piRNAs and mRNA fragments, features that resemble the pattern of piRNA amplification by the 'ping-pong' cycle. Through mapping of MIWI-RNA interactions by CLIP-seq and gene expression profiling, we found that many potential piRNA-targeted mRNAs directly interact with MIWI and show elevated expression levels in the testes of Miwi catalytic mutant mice. Reporter-based assays further revealed the importance of base pairing between piRNAs and mRNA targets and the requirement for both the slicer activity and piRNA-loading ability of MIWI in piRNA-mediated target repression. Importantly, we demonstrated that proper turnover of certain key piRNA targets is essential for sperm formation. Together, these findings reveal the siRNA-like function of the piRNA machinery in mouse testes and its central requirement for male germ cell development and maturation.

提交时间: 2016-05-12 点击量701下载量482 评论 0

4. chinaXiv:201605.01468 [pdf]

RNAcentral: an international database of ncRNA sequences

Petrov, Anton I.; Kay, Simon J. E.; Gibson, Richard; Kulesha, Eugene; Staines, Dan; Bruford, Elspeth A.; Wright, Mathew W.; Burge, Sarah; Finn, Robert D.; Kersey, Paul J.; Cochrane, Guy; Bateman, Alex; Griffiths-Jones, Sam; Harrow, Jennifer; Chan, Patricia P.; Lowe, Todd M.; Zwieb, Christian W.; Wower, Jacek; Williams, Kelly P.; Hudson, Corey M.
分类: 生物学 >> 生物物理学 >> 生物物理、生物化学与分子生物学

The field of non-coding RNA biology has been hampered by the lack of availability of a comprehensive, up-to-date collection of accessioned RNA sequences. Here we present the first release of RNAcentral, a database that collates and integrates information from an international consortium of established RNA sequence databases. The initial release contains over 8.1 million sequences, including representatives of all major functional classes. A web portal (http://rnacentral.org) provides free access to data, search functionality, cross-references, source code and an integrated genome browser for selected species.

提交时间: 2016-05-12 点击量392下载量235 评论 0

5. chinaXiv:201605.01342 [pdf]

Functional Characterization of Long Noncoding RNA Lnc_bc060912 in Human Lung Carcinoma Cells

Luo, Huaxia; Sun, Yu; Wei, Guifeng; Luo, Jianjun; Yang, Xinling; Liu, Wei; Chen, Runsheng; Luo, Huaxia; Sun, Yu; Wei, Guifeng; Yang, Xinling; Liu, Wei; Chen, Runsheng; Yang, Xinling; Guo, Mingzhou
分类: 生物学 >> 生物物理学 >> 生物物理、生物化学与分子生物学

Long noncoding RNAs (lncRNAs) are pervasively transcribed in the human genome. Recent studies suggest that the involvement of IncRNAs in human diseases could be far more prevalent than previously appreciated. Here we have identified a lncRNA termed Lnc_bc060912 whose expression is increased in human lung and other tumors. Lnc_bc060912 is 1.2 kb in length and is composed of two exons. The expression of Lncbc060912, was repressed by p53. Lnc_bc060912 suppressed cell apoptosis. Using a recently developed method for RNA-pulldown with formaldehyde cross-linking, we found that Lnc_bc060912 interacted With the two DNA damage repair proteins PARP1 and NPM1. Together, these results suggest that Lnc_bc060912, via PARP1 and NPM1, affects cell apoptosis and may play important roles in tumorigenesis and cancer progression.

提交时间: 2016-05-11 点击量325下载量209 评论 0

6. chinaXiv:201605.01301 [pdf]

The Long Noncoding RNA IncTCF7 Promotes Self-Renewal of Human Liver Cancer Stem Cells through Activation of Wnt Signaling

Wang, Yanying; Du, Ying; Zhu, Pingping; Huang, Guanling; Yan, Xinlong; Ye, Buqing; Li, Chong; Xia, Pengyan; Zhang, Geng; Fan, Zusen; He, Lei; Huang, Guanling; Fan, Zusen; Luo, Jianjun; Tian, Yong; Chen, Runsheng
分类: 生物学 >> 生物物理学

Hepatocellular carcinoma (HCC) is the most prevalent subtype of liver cancer, and it is characterized by a high rate of recurrence and heterogeneity. Liver cancer stem cells (CSCs) may well contribute to both of these pathological properties, but the mechanisms underlying their self-renewal and maintenance are poorly understood. Here, using transcriptome microarray analysis, we identified a long noncoding RNA (IncRNA) termed IncTCF7 that is highly expressed in HCC tumors and liver CSCs. LncTCF7 is required for liver CSC self-renewal and tumor propagation. Mechanistically, IncTCF7 recruits the SWI/SNF complex to the promoter of TCF7 to regulate its expression, leading to activation of Wnt signaling. Our data suggest that IncTCF7-mediated Wnt signaling primes liver CSC self-renewal and tumor propagation. In sum, therefore, we have identified an IncRNA-based Wnt signaling regulatory circuit that promotes tumorigenic activity in liver cancer stem cells, highlighting the role that IncRNAs can play in tumor growth and propagation.

提交时间: 2016-05-11 点击量549下载量410 评论 0

7. chinaXiv:201605.01284 [pdf]

Transcriptome profiling of esophageal squamous cell carcinoma reveals a long noncoding RNA acting as a tumor suppressor

Wei, Guifeng; Luo, Huaxia; Sun, Yu; Tian, Liqing; Liu, Wei; Liu, Lihui; Luo, Jianjun; Chen, Runsheng; Li, Jiagen; He, Jie
分类: 生物学 >> 生物物理学 >> 肿瘤学

Esophageal Squamous Cell Carcinoma (ESCC) is among the most common malignant cancers worldwide. In the past, extensive efforts have been made to characterize the involvement of protein-coding genes in ESCC tumorigenesis but few for long noncoding RNAs (lncRNAs). To investigate the transcriptome profile and functional relevance of lncRNAs, we performed an integrative analysis of a customized combined lncRNA-mRNA microarray and RNA-seq data on ESCCs and matched normal tissues. We identified numerous lncRNAs that were differentially expressed between the normal and tumor tissues, termed "ESCC-associated lncRNAs (ESCALs)", of which, the majority displayed restricted expression pattern. Also, a subset of ESCALs appeared to be associated with ESCC patient survival. Gene set enrichment analysis (GSEA) further suggested that over half of the ESCALs were positively- or nelgativelyassociated with metastasis. Among these, we identified a novel nuclear-retained lncRNA, named Epist, which is generally highly expressed in esophagus, and which is down-regulated during ESCC progression. Epist over-expression and knockdown studies further suggest that Epist inhibits the metastasis, acting as a tumor suppressor in ESCC. Collectively, our analysis of the ESCC transcriptome identified the potential tumor suppressing lncRNA Epist, and provided a foundation for future efforts to identify functional lncRNAs for cancerous therapeutic targeting.

提交时间: 2016-05-11 点击量662下载量260 评论 0

8. chinaXiv:201605.01236 [pdf]

Long Noncoding RNA ADINR Regulates Adipogenesis by Transcriptionally Activating C/EBP alpha

Xiao, Tengfei; Liu, Lihui; Sun, Yu; Luo, Huaxia; Chen, Runsheng; Xiao, Tengfei; Liu, Lihui; Sun, Yu; Luo, Huaxia; Chen, Runsheng; Xiao, Tengfei; Li, Hongling; Li, Tangping; Wang, Shihua; Zhao, Robert Chunhua; Liu, Lihui; Sun, Yu; Luo, Huaxia; Dalton, Stephen
分类: 生物学 >> 生物物理学

C/EBP alpha is a critical transcriptional regulator of adipogenesis. HowC/EBP alpha transcriptionis itself regulated is poorly understood, however, and remains a key question that needs to be addressed for a complete understanding of adipogenic development. Here, we identify a lncRNA, ADINR(adipogenic differentiation induced noncoding RNA), transcribed from a position similar to 450 bp upstream of the C/EBP alpha gene, that orchestrates C/EBP alpha transcriptionin vivo. Depletion of ADINR leads to a severe adipogenic defect that is rescued by overexpression of C/EBP alpha. Moreover, we reveal that ADINR RNA specifically binds to PA1 and recruits MLL3/4 histone methyl-transferase complexes so as to increase H3K4me3 and decrease H3K27me3 histone modification in the C/EBP alpha locus during adipogenesis. These results show that ADINR plays important roles in regulating the differentiation of human mesenchymal stem cells into adipocytes by modulating C/EBP alpha in cis.

提交时间: 2016-05-11 点击量335下载量222 评论 0

9. chinaXiv:201605.01231 [pdf]

Decomposition of RNA methylome reveals co-methylation patterns induced by latent enzymatic regulators of the epitranscriptome

Liu, Lian; Zhang, Shao-Wu; Zhang, Yu-Chen; Chen, Runsheng; Liu, Hui; Zhang, Lin; Chen, Runsheng; Huang, Yufei; Meng, Jia
分类: 生物学 >> 生物物理学 >> 生物物理、生物化学与分子生物学

Biochemical modifications to mRNA, especially N6-methyladenosine (m(6)A) and 5-methylcytosine (m(5)C), have been recently shown to be associated with crucial biological functions. Despite the intriguing advancements, little is known so far about the dynamic landscape of RNA methylome across different cell types and how the epitranscriptome is regulated at the system level by enzymes, i.e., RNA methyltransferases and demethylases. To investigate this issue, a meta-analysis of m(6)A MeRIP-Seq datasets collected from 10 different experimental conditions (cell type/tissue or treatment) is performed, and the combinatorial epitranscriptome, which consists of 42758 m(6)A sites, is extracted and divided into 3 clusters, in which the methylation sites are likely to be hyper- or hypo-methylated simultaneously (or co-methylated), indicating the sharing of a common methylation regulator. Four different clustering approaches are used, including K-means, hierarchical clustering (HC), Bayesian factor regression model (BFRM) and nonnegative matrix factorization (NMF) to unveil the co-methylation patterns. To validate whether the patterns are corresponding to enzymatic regulators, i.e., RNA methyltransferases or demethylases, the target sites of a known m(6)A regulator, fat mass and obesity-associated protein (FTO), are identified from an independent mouse MeRIP-Seq dataset and lifted to human. Our study shows that 3 out of the 4 clustering approaches used can successfully identify a group of methylation sites overlapping with FTO target sites at a significance level of 0.05 (after multiple hypothesis adjustment), among which, the result of NMF is the most significant (p-value 2.81 x 10(-06)). We defined a new approach evaluating the consistency between two clustering results which shows that clustering results of different methods are highly correlated strongly indicating the existence of co-methylation patterns. Consistent with recent studies, a number of cancer and neuronal disease-related bimolecular functions are enriched in the identified clusters, which are biological functions that can be regulated at the epitranscriptional level, indicating the pharmaceutical prospect of RNA N6-methyladenosine-related studies. This result successfully reveals the linkage between the global RNA co-methylation patterns embedded in the epitranscriptomic data under multiple experimental conditions and the latent enzymatic regulators, suggesting a promising direction towards a more comprehensive understanding of the epitranscriptome.

提交时间: 2016-05-11 点击量340下载量168 评论 0

10. chinaXiv:201605.01196 [pdf]

Epigenetic changes and functional study of HOXA11 in human gastric cancer

Cui, Yingying; Gao, Dan; Linghu, Enqiang; Guo, Mingzhou; Cui, Yingying; Zhan, Qimin; Zhan, Qimin; Chen, Runsheng; Brock, Malcolm V.; Herman, James G.
分类: 生物学 >> 生物物理学 >> 基因表达调控与表观遗传学

Aim: To examine epigenetic changes and the function of HOXA11 in human gastric cancer (GC). Materials & methods: Seven GC cell lines, five cases of normal gastric mucosa and 112 cases primary GC samples were used in this study. Results: Expression of HOXA11 and lack of promoter region methylation were found in NCI-N87, MKN45, BGC823 and HGC27 cells. Loss of expression and complete methylation were found in AGS gastric cancer cells. Reduced expression and partial methylation were found in MGC803 and SGC7901 cells. Restoration of HOXA11 expression was induced by 5-aza-2'-deoxycytidine. HOXA11 was methylated in 81.25% (91/112) of primary GCs. The presence of methylation was associated with male gender, tumor size, tumor differentiation and lymph node metastasis (all p < 0.05). Restoration of HOXA11 expression reduced cell proliferation, invasion, migration and induced apoptosis and G2/M phase arrest. HOXA11 was found to inhibit Wnt signaling by upregulating NKD1 expression. Conclusion: Epigenetic silencing of HOXA11 promotes GC proliferation, migration and invasion through activation of Wnt signaling.

提交时间: 2016-05-11 点击量636下载量464 评论 0

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