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Foronda M.,Telomeres and Telomerase Group | Martinez P.,Telomeres and Telomerase Group | Schoeftner S.,Telomeres and Telomerase Group | Schoeftner S.,Laboratorio Nazionale Consorzio Interuniversitario Biotecnologie | And 5 more authors.
Cell Reports | Year: 2014

Sox4 expression is restricted in mammals to embryonic structures and some adult tissues, such as lymphoid organs, pancreas, intestine, and skin. During embryogenesis, Sox4 regulates mesenchymal and neural progenitor survival, as well as lymphocyte and myeloid differentiation, and contributes to pancreas, bone, and heart development. Aberrant Sox4 expression is linked to malignant transformation and metastasis in several types of cancer. To understand the roleof Sox4 in the adult organism, we first generated mice with reduced whole-body Sox4 expression. These mice display accelerated aging and reduced cancer incidence. To specifically address a role for Sox4 in adult stem cells, we conditionally deleted Sox4 (Sox4cKO) in stratified epithelia. Sox4cKO mice show increased skin stem cell quiescence and resistance to chemical carcinogenesis concomitantly with downregulation of cell cycle, DNA repair, and activated hair follicle stem cell pathways. Altogether, these findings highlight the importance of Sox4 in regulating adult tissue homeostasis and cancer. © 2014 The Authors. Source

Gurian E.,University of Trieste | Gurian E.,Laboratorio Nazionale Consorzio Interuniversitario Biotecnologie | Bellich B.,University of Trieste | Cesaro A.,University of Trieste | Cesaro A.,Elettra - Sincrotrone Trieste
Food Hydrocolloids | Year: 2016

The isothermal dehydration of aqueous biosystems is a relevant topic in food, pharmaceutical and cosmetic industry and has been recently investigated for the assessment of a model calorimetric set-up and for the characterization of the parameters featuring the experimental calorimetric curve.In this study, the experimental Differential Scanning Calorimetry (DSC) data obtained under controlled conditions in isothermal mode have been collected on the dehydration of films consisting of solutions and gels of alginate, hydroxypropylmethylcellulose (HPMC), trehalose and mixtures thereof. Based on the proportionality between the calorimetric heat flow and water activity (aw) of solutions of known aw, the values calculated from calorimetry have been compared to those obtained with classic hygrometric measurements revealing a good consistency between the methods. Furthermore, the experimental data were mathematically turned into desorption isotherms, providing a continuous description of the water activity down to the low water activity limit. This experimental method represents an innovative approach to support other consolidated analytical techniques in the physico-chemical characterization of aqueous systems and, more importantly, a step forward in the determination of water activity as a continuous measurement in a timeframe far shorter than that necessary with other instruments (e.g., hygrometers). © 2016 Elsevier Ltd. Source

Scarola M.,Laboratorio Nazionale Consorzio Interuniversitario Biotecnologie | Comisso E.,Laboratorio Nazionale Consorzio Interuniversitario Biotecnologie | Pascolo R.,Laboratorio Nazionale Consorzio Interuniversitario Biotecnologie | Chiaradia R.,Laboratorio Nazionale Consorzio Interuniversitario Biotecnologie | And 8 more authors.
Nature Communications | Year: 2015

Pseudogene-derived, long non-coding RNAs (lncRNAs) act as epigenetic regulators of gene expression. Here we present a panel of new mouse Oct4 pseudogenes and demonstrate that the X-linked Oct4 pseudogene Oct4P4 critically impacts mouse embryonic stem cells (mESCs) self-renewal. Sense Oct4P4 transcription produces a spliced, nuclear-restricted lncRNA that is efficiently upregulated during mESC differentiation. Oct4P4 lncRNA forms a complex with the SUV39H1 HMTase to direct the imposition of H3K9me3 and HP1α to the promoter of the ancestral Oct4 gene, located on chromosome 17, leading to gene silencing and reduced mESC self-renewal. Targeting Oct4P4 expression in primary mouse embryonic fibroblasts causes the re-acquisition of self-renewing features of mESC. We demonstrate that Oct4P4 lncRNA plays an important role in inducing and maintaining silencing of the ancestral Oct4 gene in differentiating mESCs. Our data introduces a sense pseudogene-lncRNA-based mechanism of epigenetic gene regulation that controls the cross-talk between pseudogenes and their ancestral genes. © 2015 Macmillan Publishers Limited. All rights reserved. Source

Dinami R.,Laboratorio Nazionale Consorzio Interuniversitario Biotecnologie | Dinami R.,University of Trieste | Dinami R.,Telomeres in Cancer and Aging Unit | Ercolani C.,Regina Elena Cancer Institute | And 19 more authors.
Cancer Research | Year: 2014

Telomeres consist of DNA tandemrepeats that recruit the multiprotein complex shelterin to build a chromatin structure that protects chromosome ends. Although cancer formation is linked to alterations in telomere homeostasis, there is little understanding of how shelterin function is limited in cancer cells. Using a small-scale screening approach, we identified miR-155 as a key regulator in breast cancer cell expression of the shelterin component TERF1 (TRF1). miR-155 targeted a conserved sequence motif in the 30UTR of TRF1, resulting in its translational repression. miR-155 was upregulated commonly in breast cancer specimens, as associated with reduced TRF1 protein expression, metastasis-free survival, and relapse-free survival in estrogen receptor-positive cases. Modulating miR-155 expression in cells altered TRF1 levels and TRF1 abundance at telomeres. Compromising TRF1 expression by elevating miR-155 increased telomere fragility and altered the structure of metaphase chromosomes. In contrast, reducing miR-155 levels improved telomere function and genomic stability. These results implied that miR-155 upregulation antagonizes telomere integrity in breast cancer cells, increasing genomic instability linked to poor clinical outcome in estrogen receptor-positive disease. Our work argued that miRNAdependent regulation of shelterin function has a clinically significant impact on telomere function, suggesting the existence of "telo-miRNAs" that have an impact on cancer and aging. © 2014 American Association for Cancer Research. Source

Schoeftner S.,Laboratorio Nazionale Consorzio Interuniversitario Biotecnologie | Schoeftner S.,Italian National Cancer Institute | Scarola M.,Laboratorio Nazionale Consorzio Interuniversitario Biotecnologie | Comisso E.,Laboratorio Nazionale Consorzio Interuniversitario Biotecnologie | And 4 more authors.
Stem Cells | Year: 2013

The pluripotency of mouse embryonic stem cells (mESCs) is controlled by a network of transcription factors, mi-RNAs, and signaling pathways. Here, we present a new regulatory circuit that connects miR-335, Oct4, and the Retinoblastoma pathway to control mESC self-renewal and differentiation. Oct4 drives the expression of Nipp1 and Ccnf that inhibit the activity of the protein phosphatase 1 (PP1) complex to establish hyperphosphorylation of the retinoblastoma protein 1 (pRb) as a hallmark feature of self-renewing mESCs. The Oct4-Nipp1/Ccnf-PP1-pRb axis promoting mESC self-renewal is under control of miR-335 that regulates Oct4 and Rb expression. During mESC differentiation, miR-335 upregulation co-operates with the transcriptional repression of Oct4 to facilitate the collapse of the Oct4-Nipp1/Ccnf-PP1-pRb axis, pRb dephosphorylation, the exit from self-renewal, and the establishment of a pRb-regulated cell cycle program. Our results introduce Oct4-dependent control of the Rb pathway as novel regulatory circuit controlling mESC self-renewal and differentiation. © AlphaMed Press. Source

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