In Vivo Function and Evolution of the Eutherian-Specific Pluripotency Marker UTF1

Embryogenesis in placental mammals is sustained by exquisite interplay between the embryo proper and placenta. UTF1 is a developmentally regulated gene expressed in both cell lineages. Here, we analyzed the consequence of loss of the UTF1 gene during mouse development. We found that homozygous UTF1 mutant newborn mice were significantly smaller than wild-type or heterozygous mutant mice, suggesting that placental insufficiency caused by the loss of UTF1 expression in extra-embryonic ectodermal cells at least in part contributed to this phenotype. We also found that the effects of loss of UTF1 expression in embryonic stem cells on their pluripotency were very subtle. Genome structure and sequence comparisons revealed that the UTF1 gene exists only in placental mammals. Our analyses of a family of genes with homology to UTF1 revealed a possible mechanism by which placental mammals have evolved the UTF1 genes.This study was supported in part by the Japanese Ministry of Education, Culture, Sports, Science and Technology (MEXT), and mostly by the Support Program for the Strategic Research Foundation at Private Universities, 2008–2012. This study was performed as a part of the Core Research for Evolutional Science and Technology (CREST) Agency. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

Identification of novel oncogenes in oral cancer among elderly nonsmokers

Abstract Objectives In recent years, an increase in oral cancer among elderly nonsmokers has been noted. The aim of this study was to identify novel oncogenes in oral cancer in older nonsmokers. Material and Methods Whole‐exome sequencing (WES) data from 324 oral cancer patients were obtained from The Cancer Genome Atlas. Single nucleotide variants (SNVs) and insertions/deletions (INDELs) were extracted from the WES data of older patients. Fisher's exact test was performed to determine the specificity of variants in these genes. Finally, SNVs and INDELs were identified by target enrichment sequencing. Results Gene ontology analysis of 112 genes with significant SNVs or INDELs in nonsmokers revealed that nonsynonymous SNVs in HECTD4 were significantly more frequent in nonsmokers than in smokers by target enrichment sequencing (p = .02). Conclusions Further investigation of the function of HECTD4 variants as oncogenes in older nonsmokers is warranted

Striking Similarity in the Gene Expression Levels of Individual Myc Module Members among ESCs, EpiSCs, and Partial iPSCs

<div><p>Predominant transcriptional subnetworks called Core, Myc, and PRC modules have been shown to participate in preservation of the pluripotency and self-renewality of embryonic stem cells (ESCs). Epiblast stem cells (EpiSCs) are another cell type that possesses pluripotency and self-renewality. However, the roles of these modules in EpiSCs have not been systematically examined to date. Here, we compared the average expression levels of Core, Myc, and PRC module genes between ESCs and EpiSCs. EpiSCs showed substantially higher and lower expression levels of PRC and Core module genes, respectively, compared with those in ESCs, while Myc module members showed almost equivalent levels of average gene expression. Subsequent analyses revealed that the similarity in gene expression levels of the Myc module between these two cell types was not just overall, but striking similarities were evident even when comparing the expression of individual genes. We also observed equivalent levels of similarity in the expression of individual Myc module genes between induced pluripotent stem cells (iPSCs) and partial iPSCs that are an unwanted byproduct generated during iPSC induction. Moreover, our data demonstrate that partial iPSCs depend on a high level of c-Myc expression for their self-renewal properties.</p> </div

Most Myc module members maintain constant levels of expression in naïve and primed human iPSCs.

<div><p>(A) Average gene expression values (log₂) of Core, Myc, and PRC module genes in primed human iPSCs using those in human iPSCs converted to a naïve state as references <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0083769#B33" target="_blank">33</a>. Data from 69 Core, 321 Myc, and 423 PRC module genes deposited in GEO under GSE21222 were used for the analyses. Data from six Core, 34 Myc, and 28 PRC module genes are not available in the deposited data sets.</p> <p>(B) Comparison of the expression of individual Core, Myc, and PRC module genes between naïve and primed human iPSCs. Left, middle, and right scatter plots show the expression values of individual Core, Myc, and PRC module genes, respectively, in naïve and primed human iPSCs. Red and blue spots indicate genes with expression levels that are higher or lower by more than 2-fold in primed human iPSCs compared with those in naïve human iPSCs, respectively. Gene symbols corresponding to red and blue are listed in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0083769#pone.0083769.s014" target="_blank">Table S5</a>. The variance value was calculated and is shown for each scatter plot.</p> <p>(C) Scatter plot analyses of the selected genes from Core (left), Myc (middle), and PRC (right) modules. The same sets of genes (<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0083769#pone.0083769.s012" target="_blank">Table S3</a>) used in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0083769#pone-0083769-g001" target="_blank">Figure 1C</a> were used for the analyses. The data lacked information for 15, 33, and 13 genes of the selected Core (50), Myc (98), and PRC (115) module genes, respectively. Red and blue spots indicate as described in B.</p></div

Highly specific activation of Core and Myc modules and repression of the PRC module in pluripotent cells.

<p>Publicly available DNA microarray data for 20 different tissue/somatic cell and stem cell types were obtained from the NCBI GEO database. To compare the same sets of genes used in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0083769#pone-0083769-g001" target="_blank">Figures 1</a> and <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0083769#pone-0083769-g002" target="_blank">2</a>, data obtained using the same DNA microarray platform (Mouse Expression Array 430 platform, Affymetrix) by Hayashi et al. [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0083769#B29" target="_blank">29</a>] were selected from the database. Average gene expression values (log₂) of Core (upper panel), Myc (meddle panel), and PRC (lower panel) modules in each sample were calculated using those in ESCs as references. The data were aligned in an ordered fashion based on the value of average Myc module gene expression in which a sample showing the highest score, i.e., gPSC, was put at the left end of graph. The accession numbers of the obtained DNA microarray data are listed in the Materials and Methods. Data from germline stem cells and their derivatives, somatic stem cells, tissues, terminally differentiated hematopoietic cells and EpiSCs/EpiLCs are indicated by pink, blue, green, red, and gray bars, respectively, in the graph.</p

Comparison of the expression of Core and Myc module genes in EpiSCs and ESCs.

<div><p>(A) Average gene expression values (log₂) of Core, Myc, and PRC module genes in EpiSCs using values from ESCs as references. Data from 99 Core, 426 Myc, and 474 PRC module genes deposited in GEO under GSE30056 were used for the analyses. Data from 12 Core (111 genes), 77 Myc (503 genes), and 86 PRC (560) module genes are not available in the deposited data sets.</p> <p>(B) Comparison of the expression of individual Core, Myc, and PRC module genes between ESCs and EpiSCs. Left, middle, and right scatter plots show the expression values of individual Core, Myc, and PRC module genes, respectively, in ESCs and EpiSCs. Red and blue spots indicate genes with expression levels that are higher or lower by more than 2-fold in EpiSCs compared with those in ESCs, respectively. Gene symbols corresponding to red and blue are listed in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0083769#pone.0083769.s011" target="_blank">Table S2</a>. The variance value was calculated and is shown for each scatter plot.</p> <p>(C) Left, middle, and right scatter plots show the expression values of the selected Core, Myc, and Core module genes (listed in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0083769#pone.0083769.s012" target="_blank">Table S3</a>), respectively, in ESCs and EpiSCs. Red and blue spots indicate as described in B. The variance value was calculated and is shown for each scatter plot.</p></div

PTEN-induced kinase 1 gene single-nucleotide variants as biomarkers in adjuvant chemotherapy for colorectal cancer: a retrospective study

Abstract Background Fluoropyrimidine-based postoperative adjuvant chemotherapy is globally recommended for high-risk stage II and stage III colon cancer. However, adjuvant chemotherapy is often associated with severe adverse events and is not highly effective in preventing recurrence. Therefore, discovery of novel molecular biomarkers of postoperative adjuvant chemotherapy to identify patients at increased risk of recurrent colorectal cancer is warranted. Autophagy (including mitophagy) is activated under chemotherapy-induced stress and contributes to chemotherapy resistance. Expression of autophagy-related genes and their single-nucleotide polymorphisms are reported to be effective predictors of chemotherapy response in some cancers. Our goal was to evaluate the relationship between single-nucleotide variants of autophagy-related genes and recurrence rates in order to identify novel biomarkers that predict the effect of adjuvant chemotherapy in colorectal cancer. Methods We analyzed surgical or biopsy specimens from 84 patients who underwent radical surgery followed by fluoropyrimidine-based adjuvant chemotherapy at Saitama Medical University International Medical Center between January and December 2016. Using targeted enrichment sequencing, we identified single-nucleotide variants and insertions/deletions in 50 genes, including autophagy-related genes, and examined their association with colorectal cancer recurrence rates. Results We detected 560 single-nucleotide variants and insertions/deletions in the target region. The results of Fisher’s exact test indicated that the recurrence rate of colorectal cancer after adjuvant chemotherapy was significantly lower in patients with the single-nucleotide variants (c.1018G > A [p  C [p < 0.01]) of the mitophagy-related gene PTEN-induced kinase 1. Conclusions The two single-nucleotide variants of PINK1 gene may be biomarkers of non-recurrence in colorectal cancer patients who received postoperative adjuvant chemotherapy