Correction: In Vivo Tumorigenesis Was Observed after Injection of In Vitro Expanded Neural Crest Stem Cells Isolated from Adult Bone Marrow.

[This corrects the article DOI: 10.1371/journal.pone.0046425.]

Delayed neuroendocrine sexual maturation in female rats after a very low dose of Bisphenol A through altered GABAergic neurotransmission and opposing effects of a high dose.

Rat sexual maturation is preceded by a reduction of the interpulse interval (IPI) of gonadotropinreleasing hormone (GnRH) neurosecretion. This work aims at studying disruption of that neuroendocrine event in females after early exposure to a very low dose of Bisphenol A (BPA), a ubiquitous endocrine disrupting chemical. Female rats were exposed to vehicle or BPA 25 ng/kg.day, 25 g/kg.day, or 5 mg/kg.day from postnatal day (PND) 1 to 5 or 15. Exposure to 25 ng/kg.day of BPA for 5 or 15 days was followed by a delay in developmental reduction of GnRH IPI studied ex vivo on PND 20. After 15 days of exposure to that low dose of BPA, vaginal opening tended to be delayed. In contrast, exposure to BPA 5 mg/kg.day for 15 days resulted in a premature reduction inGnRHIPI and a trend toward early vaginal opening. RNAseq analysis on PND20 indicated that exposure to BPA resulted in opposing dose effectsonthemRNAexpression of hypothalamic genes involved inGABAA neurotransmission. The study of GnRH secretion in vitro in the presence of GABAA receptor agonist/antagonist confirmed an increased or a reduced GABAergic tone after in vivo exposure to the very low or the high dose of BPA, respectively. Overall, we show for the first time that neonatal exposure to BPA leads to opposing dose-dependent effects on the neuroendocrine control of puberty in the female rat. A very low and environmentally relevant dose of BPA delays neuroendocrine maturation related to puberty through increased inhibitory GABAergic neurotransmission

Role of the splicing factor SRSF4 in cisplatin-induced modifications of pre-mRNA splicing and apoptosis.

BACKGROUND: Modification of splicing by chemotherapeutic drugs has usually been evaluated on a limited number of pre-mRNAs selected for their recognized or potential importance in cell proliferation or apoptosis. However, the pathways linking splicing alterations to the efficiency of cancer therapy remain unclear. METHODS: Next-generation sequencing was used to analyse the transcriptome of breast carcinoma cells treated by cisplatin. Pharmacological inhibitors, RNA interference, cells deficient in specific signalling pathways, RT-PCR and FACS analysis were used to investigate how the anti-cancer drug cisplatin affected alternative splicing and the cell death pathway. RESULTS: We identified 717 splicing events affected by cisplatin, including 245 events involving cassette exons. Gene ontology analysis indicates that cell cycle, mRNA processing and pre-mRNA splicing were the main pathways affected. Importantly, the cisplatin–induced splicing alterations required class I PI3Ks P110β but not components such as ATM, ATR and p53 that are involved in the DNA damage response. The siRNA-mediated depletion of the splicing regulator SRSF4, but not SRSF6, expression abrogated many of the splicing alterations as well as cell death induced by cisplatin. CONCLUSION: Many of the splicing alterations induced by cisplatin are caused by SRSF4 and they contribute to apoptosis in a process requires class I PI3K. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12885-015-1259-0) contains supplementary material, which is available to authorized users

Disruption of GnRH secretion in peripubertal female rat after early postnatal exposure to Bisphenol A and involvement of GPR151, a potential new GnRH regulator

peer reviewe

In vivo tumorigenesis was observed after injection of in vitro expanded neural crest stem cells isolated from adult bone marrow

Bone marrow stromal cells are adult multipotent cells that represent an attractive tool in cellular therapy strategies. Several studies have reported that in vitro passaging of mesenchymal stem cells alters the functional and biological properties of those cells, leading to the accumulation of genetic aberrations. Recent studies described bone marrow stromal cells (BMSC) as mixed populations of cells including mesenchymal (MSC) and neural crest stem cells (NCSC). Here, we report the transformation of NCSC into tumorigenic cells, after in vitro long-term passaging. Indeed, the characterization of 6 neural crest-derived clones revealed the presence of one tumorigenic clone. Transcriptomic analyses of this clone highlighted, among others, numerous cell cycle checkpoint modifications and chromosome 11q down-regulation (suggesting a deletion of chromosome 11q) compared with the other clones. Moreover, unsupervised analysis such as a dendrogram generated after agglomerative hierarchical clustering comparing several transcriptomic data showed important similarities between the tumorigenic neural crest-derived clone and mammary tumor cell lines. Altogether, it appeared that NCSC isolated from adult bone marrow represents a potential danger for cellular therapy, and consequently, we recommend that phenotypic, functional and genetic assays should be performed on bone marrow mesenchymal and neural crest stem cells before in vivo use, to demonstrate whether their biological properties, after ex vivo expansion, remain suitable for clinical application

Epigenetic program and transcription factor circuitry of dendritic cell development

Dendritic cells (DC) are professional antigen presenting cells that develop from hematopoietic stem cells through successive steps of lineage commitment and differentiation. Multipotent progenitors (MPP) are committed to DC restricted common DC progenitors (CDP), which differentiate into specific DC subsets, classical DC (cDC) and plasmacytoid DC (pDC). To determine epigenetic states and regulatory circuitries during DC differentiation, we measured consecutive changes of genome-wide gene expression, histone modification and transcription factor occupancy during the sequel MPP-CDP-cDC/pDC. Specific histone marks in CDP reveal a DC-primed epigenetic signature, which is maintained and reinforced during DC differentiation. Epigenetic marks and transcription factor PU.1 occupancy increasingly coincide upon DC differentiation. By integrating PU.1 occupancy and gene expression we devised a transcription factor regulatory circuitry for DC commitment and subset specification. The circuitry provides the transcription factor hierarchy that drives the sequel MPP-CDP-cDC/pDC, including Irf4, Irf8, Tcf4, Spib and Stat factors. The circuitry also includes feedback loops inferred for individual or multiple factors, which stabilize distinct stages of DC development and DC subsets. In summary, here we describe the basic regulatory circuitry of transcription factors that drives DC development

Dendrogram from agglomerative hierarchical clustering of Asclepios and several cell types, including tumor cell lines.

<p>Dendrogram generated after agglomerative hierarchical clustering using Euclidean distance, complete linkage and multiscale bootstrap resampling. 61 expression arrays were included in an unsupervised analysis with hierarchical clustering of samples. Spontaneous epithelial mammary tumor cell lines (SEMTCL - GSE13259); Tumor cell lines 67NR, 66cl4 and 4T1 (TCL67NR, TCL66cl4 and TCL4T1 - GSE11259); Embryonal tumor deriving from neural crest cells (NCCE85, NCCE135, NCCP90 - GSE11356); Multipotent adult progenitor cells (MAPC - GSE6291); Developing Heart (DH - GSE7196); Neural precursors obtained from embryonic stem cells (NPFES - GSE8024); White and brown adipose (WAA, BAA - GSE8044); Head Neck Neural Crest Stem Cells (E115FAKCtle1 - GSE11149); Murine acute myeloid leukemia (UAML - GSE30747). Datasets are accessible on GEO datasets/NCBI (<a href="http://www.ncbi.nlm.nih.gov/gds" target="_blank">http://www.ncbi.nlm.nih.gov/gds</a>). The dendrogram was built with the Euclidean distance as dissimilarity metric and the complete linkage method for definition of the structure. Values on the edges of the clustering are <i>p</i>-values (%). Red values are <b>AU </b><i>p</i>-values and green values are <b>BP</b> values. AU (Approximately Unbiased) <i>p</i>-values were computed by multiscale bootstrap resampling. BP (Bootstrap Probability) values were computed by normal bootstrap resampling. R-cran “pvclust” package was used for assessing the uncertainty of this hierarchical cluster analysis for 10,000 permutations of genes. Those values indicated how strongly the cluster was supported by the data.</p