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Sant'Ambrogio di Torino, Italy

Riba A.,University of Turin | Bosia C.,University of Turin | El Baroudi M.,Human Genetics Foundation HuGeF | El Baroudi M.,CNR Institute of Clinical Physiology | And 2 more authors.
PLoS Computational Biology | Year: 2014

It is well known that, under suitable conditions, microRNAs are able to fine tune the relative concentration of their targets to any desired value. We show that this function is particularly effective when one of the targets is a Transcription Factor (TF) which regulates the other targets. This combination defines a new class of feed-forward loops (FFLs) in which the microRNA plays the role of master regulator. Using both deterministic and stochastic equations, we show that these FFLs are indeed able not only to fine-tune the TF/target ratio to any desired value as a function of the miRNA concentration but also, thanks to the peculiar topology of the circuit, to ensure the stability of this ratio against stochastic fluctuations. These two effects are due to the interplay between the direct transcriptional regulation and the indirect TF/Target interaction due to competition of TF and target for miRNA binding (the so called "sponge effect"). We then perform a genome wide search of these FFLs in the human regulatory network and show that they are characterized by a very peculiar enrichment pattern. In particular, they are strongly enriched in all the situations in which the TF and its target have to be precisely kept at the same concentration notwithstanding the environmental noise. As an example we discuss the FFL involving E2F1 as Transcription Factor, RB1 as target and miR-17 family as master regulator. These FFLs ensure a tight control of the E2F/RB ratio which in turns ensures the stability of the transition from the G0/G1 to the S phase in quiescent cells. © 2014 Riba et al.

Pagnani A.,Human Genetics Foundation HuGeF | Parisi G.,University of Rome La Sapienza
Physical Review E - Statistical, Nonlinear, and Soft Matter Physics | Year: 2013

We study the restricted solid-on-solid model for surface growth in spatial dimension d=4 by means of a multisurface coding technique that allows us to analyze samples of size up to 2564 in the steady-state regime. For such large systems we are able to achieve a controlled asymptotic regime where the typical scale of the fluctuations are larger than the lattice spacing used in the simulations. A careful finite-size scaling analysis of the critical exponents clearly indicate that d=4 is not the upper critical dimension of the model. © 2013 American Physical Society.

Incarnato D.,Human Genetics Foundation HuGeF | Incarnato D.,University of Siena | Neri F.,Human Genetics Foundation HuGeF | Anselmi F.,Human Genetics Foundation HuGeF | And 2 more authors.
Genome Biology | Year: 2014

Background: The understanding of RNA structure is a key feature toward the comprehension of RNA functions and mechanisms of action. In particular, non-coding RNAs are thought to exert their functions by specific secondary structures, but an efficient annotation on a large scale of these structures is still missing. Results: By using a novel high-throughput method, named chemical inference of RNA structures, CIRS-seq, that uses dimethyl sulfate, and N-cyclohexyl- N'-(2-morpholinoethyl)carbodiimide metho-p-toluenesulfonate to modify RNA residues in single-stranded conformation within native deproteinized RNA secondary structures, we investigate the structural features of mouse embryonic stem cell transcripts. Our analysis reveals an unexpected higher structuring of the 5' and 3' untranslated regions compared to the coding regions, a reduced structuring at the Kozak sequence and stop codon, and a three-nucleotide periodicity across the coding region of messenger RNAs. We also observe that ncRNAs exhibit a higher degree of structuring with respect to protein coding transcripts. Moreover, we find that the Lin28a binding protein binds selectively to RNA motifs with a strong preference toward a single stranded conformation. Conclusions: This work defines for the first time the complete RNA structurome of mouse embryonic stem cells, revealing an extremely distinct RNA structural landscape. These results demonstrate that CIRS-seq constitutes an important tool for the identification of native deproteinized RNA structures. © Incarnato et al.

Neri F.,Human Genetics Foundation HuGeF | Incarnato D.,University of Turin | Krepelova A.,Human Genetics Foundation HuGeF | Dettori D.,Human Genetics Foundation HuGeF | And 6 more authors.
Nucleic acids research | Year: 2015

Ten-eleven translocation (Tet) genes encode for a family of hydroxymethylase enzymes involved in regulating DNA methylation dynamics. Tet1 is highly expressed in mouse embryonic stem cells (ESCs) where it plays a critical role the pluripotency maintenance. Tet1 is also involved in cell reprogramming events and in cancer progression. Although the functional role of Tet1 has been largely studied, its regulation is poorly understood. Here we show that Tet1 gene is regulated, both in mouse and human ESCs, by the stemness specific factors Oct3/4, Nanog and by Myc. Thus Tet1 is integrated in the pluripotency transcriptional network of ESCs. We found that Tet1 is switched off by cell proliferation in adult cells and tissues with a consequent genome-wide reduction of 5hmC, which is more evident in hypermethylated regions and promoters. Tet1 downmodulation is mediated by the Polycomb repressive complex 2 (PRC2) through H3K27me3 histone mark deposition. This study expands the knowledge about Tet1 involvement in stemness circuits in ESCs and provides evidence for a transcriptional relationship between Tet1 and PRC2 in adult proliferating cells improving our understanding of the crosstalk between the epigenetic events mediated by these factors. © The Author(s) 2015. Published by Oxford University Press on behalf of Nucleic Acids Research.

Incarnato D.,Human Genetics Foundation HuGeF | Incarnato D.,University of Siena | Krepelova A.,Human Genetics Foundation HuGeF | Neri F.,Human Genetics Foundation HuGeF
Genomics | Year: 2014

Mouse E14 embryonic stem cells (ESCs) are a well-characterized and widespread used ESC line, often employed for genome-wide studies involving next generation sequencing analysis. More than 2×109 sequences made on Illumina platform derived from the genome of E14 ESCs were used to build a database of about 2.7×106 single nucleotide variants (SNVs). The identified variants are enriched in intergenic regions, but several thousands reside in gene exons and regulatory regions, such as promoters, enhancers, splicing sites and untranslated regions of RNA, thus indicating high probability of an important functional impact on the molecular biology of these cells. We created a new E14 genome assembly reference that increases the number of mapped reads of about 5%. We performed a Reduced Representation Bisulfite Sequencing on E14 ESCs and we obtained an increase of about 120,000 called CpGs and avoided about 20,000 wrong CpG calls with respect to the mm9 genome reference. © 2014 Elsevier Inc.

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