Rif1 Maintains Telomere Length Homeostasis of ESCs by Mediating Heterochromatin Silencing

SummaryTelomere length homeostasis is essential for genomic stability and unlimited self-renewal of embryonic stem cells (ESCs). We show that telomere-associated protein Rif1 is required to maintain telomere length homeostasis by negatively regulating Zscan4 expression, a critical factor for telomere elongation by recombination. Depletion of Rif1 results in terminal hyperrecombination, telomere length heterogeneity, and chromosomal fusions. Reduction of Zscan4 by shRNA significantly rescues telomere recombination defects of Rif1-depleted ESCs and associated embryonic lethality. Further, Rif1 negatively modulates Zscan4 expression by maintaining H3K9me3 levels at subtelomeric regions. Mechanistically, Rif1 interacts and stabilizes H3K9 methylation complex. Thus, Rif1 regulates telomere length homeostasis of ESCs by mediating heterochromatic silencing

Impact of Ferrous Iron on Microbial Community of the Biofilm in Microbial Fuel Cells

The performance of microbial electrochemical cells depends upon microbial community structure and metabolic activity of the electrode biofilms. Iron as a signal affects biofilm development and enrichment of exoelectrogenic bacteria. In this study, the effect of ferrous iron on microbial communities of the electrode biofilms in microbial fuel cells (MFCs) was investigated. Voltage production showed that ferrous iron of 100 μM facilitated MFC start-up compared to 150 μM, 200 μM, and without supplement of ferrous iron. However, higher concentration of ferrous iron had an inhibitive influence on current generation after 30 days of operation. Illumina Hiseq sequencing of 16S rRNA gene amplicons indicated that ferrous iron substantially changed microbial community structures of both anode and cathode biofilms. Principal component analysis showed that the response of microbial communities of the anode biofilms to higher concentration of ferrous iron was more sensitive. The majority of predominant populations of the anode biofilms in MFCs belonged to Geobacter, which was different from the populations of the cathode biofilms. An obvious shift of community structures of the cathode biofilms occurred after ferrous iron addition. This study implied that ferrous iron influenced the power output and microbial community of MFCs

Influences of lamin A levels on induction of pluripotent stem cells

Summary Lamin A is an inner nuclear membrane protein that maintains nuclear structure integrity, is involved in transcription, DNA damage response and genomic stability, and also links to cell differentiation, senescence, premature aging and associated diseases. Induced pluripotent stem (iPS) cells have been successfully generated from various types of cells and used to model human diseases. It remains unclear whether levels of lamin A influence reprogramming of somatic cells to pluripotent states during iPS induction. Consistently, lamin A is expressed more in differentiated than in relatively undifferentiated somatic cells, and increases in expression levels with age. Somatic cells with various expression levels of lamin A differ in their dynamics and efficiency during iPS cell induction. Cells with higher levels of lamin A show slower reprogramming and decreased efficiency to iPS cells. Furthermore, depletion of lamin A by transient shRNA accelerates iPS cell induction from fibroblasts. Reduced levels of lamin A are associated with increased expression of pluripotent genes Oct4 and Nanog, and telomerase genes Tert and Terc. On the contrary, overexpression of lamin A retards somatic cell reprogramming to iPS-like colony formation. Our data suggest that levels of lamin A influence reprogramming of somatic cells to pluripotent stem cells and that artificial silencing of lamin A facilitates iPS cell induction. These findings may have implications in enhancing rejuvenation of senescent or older cells by iPS technology and manipulating lamin A levels

Correction: Intrahepatic Tissue Implantation Represents a Favorable Approach for Establishing Orthotopic Transplantation Hepatocellular Carcinoma Mouse Models.

[This corrects the article DOI: 10.1371/journal.pone.0148263.]

Intrahepatic Tissue Implantation Represents a Favorable Approach for Establishing Orthotopic Transplantation Hepatocellular Carcinoma Mouse Models.

Mouse models are commonly used for studying hepatocellular carcinoma (HCC) biology and exploring new therapeutic interventions. Currently three main modalities of HCC mouse models have been extensively employed in pre-clinical studies including chemically induced, transgenic and transplantation models. Among them, transplantation models are preferred for evaluating in vivo drug efficacy in pre-clinical settings given the short latency, uniformity in size and close resemblance to tumors in patients. However methods used for establishing orthotopic HCC transplantation mouse models are diverse and fragmentized without a comprehensive comparison. Here, we systemically evaluate four different approaches commonly used to establish HCC mice in preclinical studies, including intravenous, intrasplenic, intrahepatic inoculation of tumor cells and intrahepatic tissue implantation. Four parameters--the latency period, take rates, pathological features and metastatic rates--were evaluated side-by-side. 100% take rates were achieved in liver with intrahepatic, intrasplenic inoculation of tumor cells and intrahepatic tissue implantation. In contrast, no tumor in liver was observed with intravenous injection of tumor cells. Intrahepatic tissue implantation resulted in the shortest latency with 0.5 cm (longitudinal diameter) tumors found in liver two weeks after implantation, compared to 0.1cm for intrahepatic inoculation of tumor cells. Approximately 0.1cm tumors were only visible at 4 weeks after intrasplenic inoculation. Uniform, focal and solitary tumors were formed with intrahepatic tissue implantation whereas multinodular, dispersed and non-uniform tumors produced with intrahepatic and intrasplenic inoculation of tumor cells. Notably, metastasis became visible in liver, peritoneum and mesenterium at 3 weeks post-implantation, and lung metastasis was visible after 7 weeks. T cell infiltration was evident in tumors, resembling the situation in HCC patients. Our study demonstrated that orthotopic HCC mouse models established via intrahepatic tissue implantation authentically reflect clinical manifestations in HCC patients pathologically and immunologically, suggesting intrahepatic tissue implantation is a preferable approach for establishing orthotopic HCC mouse models

Overexpression of NOTCH-regulated Ankyrin Repeat Protein is associated with papillary thyroid carcinoma progression

<div><p>Papillary thyroid cancer (PTC) is one of the endocrine cancers with high clinical and genetic heterogeneity. NOTCH signaling and its downstream NOTCH-Regulated Ankyrin Repeat Protein (NRARP) have been implicated in oncogenesis of many cancers, but the roles in PTCs are less studied. In this study, we show that NRARP is frequently over-expressed in thyroid carcinoma. The over-activation of NRARP is highly and positively correlated with NOTCH genes. Moreover, we find that the expression of NRARP is highly associated with several epithelial mesenchymal transition (EMT) markers and contributes to poor survival outcomes. Therefore, these results indicate that NRARP is an important clinical biomarker in thyroid carcinoma and it promotes EMT induction as well as the progression of PTCs via NOTCH signaling activation.</p></div

Expression correlation between NRARP and NOTCH signaling.

<p>A) Enriched pathways that are positively correlated with NRARP. B) Scatter plot of NRARP expression and NOTCH1 expression in TCGA THCA dataset. Each point stands for one tumor patient, of which values in X-axis and Y-axis represent NOTCH1 and NRARP expression, respectively. C) Scatter plots of NRARP and NOTCH3 genes. D) Scatter plots of NRARP and NOTCH4. E) Protein interaction between NRARP and NOTCH genes.</p

Over-expression of NRARP in thyroid tumors.

<p>A) Up-regulated pathways in TCGA THCA dataset. B) Boxplot of NRARP expression profiles in TCGA THCA dataset. C) Boxplot of NRARP expression profiles in public dataset GSE64912. D) Genomic alteration frequency of NRARP in TCGA THCA dataset. Each cell stands for the tumor patient.</p

Proposed model regulatory model of NRARP in thyroid cancer patients.

<p>NRARP and NOTCH related genes are up-regulated in tumor patients and contribute to tumor progression. See <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0167782#sec013" target="_blank">discussion</a> for details.</p