Poly(ADP-ribosyl)ation Acts in the DNA Demethylation of Mouse Primordial Germ Cells Also with DNA Damage-Independent Roles

Poly(ADP-ribosyl)ation regulates chromatin structure and transcription driving epigenetic events. In particular, Parp1 is able to directly influence DNA methylation patterns controlling transcription and activity of Dnmt1. Here, we show that ADP-ribose polymer levels and Parp1 expression are noticeably high in mouse primordial germ cells (PGCs) when the bulk of DNA demethylation occurs during germline epigenetic reprogramming in the embryo. Notably, Parp1 activity is stimulated in PGCs even before its participation in the DNA damage response associated with active DNA demethylation. We demonstrate that PARP inhibition impairs both genome-wide and locus-specific DNA methylation erasure in PGCs. Moreover, we evidence that impairment of PARP activity causes a significant reduction of expression of the gene coding for Tet1 hydroxylases involved in active DNA demethylation. Taken together these results demonstrate new and adjuvant roles of poly(ADP-ribosyl)ation during germline DNA demethylation and suggest its possible more general involvement in genome reprogramming

Higher-Order Partial Least Squares (HOPLS) : a generalized multi-linear regression method

A new generalized multilinear regression model, termed the Higher-Order Partial Least Squares (HOPLS), is introduced with the aim to predict a tensor (multiway array) Y from a tensor X through projecting the data onto the latent space and performing regression on the corresponding latent variables. HOPLS differs substantially from other regression models in that it explains the data by a sum of orthogonal Tucker tensors, while the number of orthogonal loadings serves as a parameter to control model complexity and prevent overfitting. The low dimensional latent space is optimized sequentially via a deflation operation, yielding the best joint subspace approximation for both X and Y. Instead of decomposing X and Y individually, higher order singular value decomposition on a newly defined generalized cross-covariance tensor is employed to optimize the orthogonal loadings. A systematic comparison on both synthetic data and real-world decoding of 3D movement trajectories from electrocorticogram (ECoG) signals demonstrate the advantages of HOPLS over the existing methods in terms of better predictive ability, suitability to handle small sample sizes, and robustness to noise.Fil: Zhao, Qibin . RIKEN Brain Science Institute; JapónFil: Caiafa, Cesar Federico. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico La Plata. Instituto Argentino de Radioastronomia (i); ArgentinaFil: Mandic, Danilo P. . Imperial College Of Science And Technology; Reino UnidoFil: Chao, Zenas C. . RIKEN Brain Science Institute; JapónFil: Nagasaka, Yasuo . RIKEN Brain Science Institute; JapónFil: Fujii, Naotaka. RIKEN Brain Science Institute; JapónFil: Zhang, Liqing. Shanghai Jiao Tong University; ChinaFil: Cichocki, Andrzej. RIKEN Brain Science Institute; Japó

Caracterização dos solos em duas toposseqüências sobre diferentes litologias em áreas altimontanas na Serra da Mantiqueira.

Estudo de solos em duas toposseqüências em áreas de preservação ambiental na Serra da Mantiqueira, a primeira localizada no Parque Estadual do Ibitipoca, município de Lima Duarte, MG e a segunda localizada na RPPN do Matutú, município de Aiuruoca, MG.bitstream/CNPS/11573/1/doc57_2003_topossequencias.pd

Analysis of the machinery and intermediates of the 5hmC-mediated DNA demethylation pathway in aging on samples from the MARKAGE Study

Gradual changes in the DNA methylation landscape occur throughout aging virtually in all human tissues. A widespread reduction of 5-methylcytosine (5mC), associated with highly reproducible site-specific hypermethylation, characterizes the genome in aging. Therefore, an equilibrium seems to exist between general and directional deregulating events concerning DNA methylation controllers, which may underpin the age-related epigenetic changes. In this context, 5mC-hydroxylases (TET enzymes) are new potential players. In fact, TETs catalyze the stepwise oxidation of 5mC to 5-hydroxymethylcytosine (5hmC), 5-formylcytosine (5fC) and 5-carboxylcytosine (5caC), driving the DNA demethylation process based on thymine DNA glycosylase (TDG)-mediated DNA repair pathway. The present paper reports the expression of DNA hydroxymethylation components, the levels of 5hmC and of its derivatives in peripheral blood mononuclear cells of age-stratified donors recruited in several European countries in the context of the EU Project ‘MARK-AGE’. The results provide evidence for an age-related decline of TET1, TET3 and TDG gene expression along with a decrease of 5hmC and an accumulation of 5caC. These associations were independent of confounding variables, including recruitment center, gender and leukocyte composition. The observed impairment of 5hmC-mediated DNA demethylation pathway in blood cells may lead to aberrant transcriptional programs in the elderly

Age-dependent expression of DNMT1 and DNMT3B in PBMCs from a large European population enrolled in the MARK-AGE study

Aging is associated with alterations in the content and patterns of DNA methylation virtually throughout the entire human lifespan. Reasons for these variations are not well understood. However, several lines of evidence suggest that the epigenetic instability in aging may be traced back to the alteration of the expression of DNA methyltransferases. Here, the association of the expression of DNA methyltransferases DNMT1 and DNMT3B with age has been analysed in the context of the MARK-AGE study, a large-scale cross-sectional study of the European general population. Using peripheral blood mononuclear cells, we assessed the variation of DNMT1 and DNMT3B gene expression in more than two thousand age-stratified women and men (35-75 years) recruited across eight European countries. Significant age-related changes were detected for both transcripts. The level of DNMT1 gradually dropped with aging but this was only observed up to the age of 64 years. By contrast, the expression of DNMT3B decreased linearly with increasing age and this association was particularly evident in females. We next attempted to trace the age-related changes of both transcripts to the influence of different variables that have an impact on changes of their expression in the population, including demographics, dietary and health habits, and clinical parameters. Our results indicate that age affects the expression of DNMT1 and DNMT3B as an almost independent variable in respect of all other variables evaluated

A Fast Gradient Approximation for Nonlinear Blind Signal Processing

When dealing with nonlinear blind processing algorithms (deconvolution or post-nonlinear source separation), complex mathematical estimations must be done giving as a result very slow algorithms. This is the case, for example, in speech processing, spike signals deconvolution or microarray data analysis. In this paper, we propose a simple method to reduce computational time for the inversion of Wiener systems or the separation of post-nonlinear mixtures, by using a linear approximation in a minimum mutual information algorithm. Simulation results demonstrate that linear spline interpolation is fast and accurate, obtaining very good results (similar to those obtained without approximation) while computational time is dramatically decreased. On the other hand, cubic spline interpolation also obtains similar good results, but due to its intrinsic complexity, the global algorithm is much more slow and hence not useful for our purpose

Parp1 Localizes within the Dnmt1 Promoter and Protects Its Unmethylated State by Its Enzymatic Activity

Aberrant hypermethylation of CpG islands in housekeeping gene promoters and widespread genome hypomethylation are typical events occurring in cancer cells. The molecular mechanisms behind these cancer-related changes in DNA methylation patterns are not well understood. Two questions are particularly important: (i) how are CpG islands protected from methylation in normal cells, and how is this protection compromised in cancer cells, and (ii) how does the genome-wide demethylation in cancer cells occur. The latter question is especially intriguing since so far no DNA demethylase enzyme has been found.Our data show that the absence of ADP-ribose polymers (PARs), caused by ectopic over-expression of poly(ADP-ribose) glycohydrolase (PARG) in L929 mouse fibroblast cells leads to aberrant methylation of the CpG island in the promoter of the Dnmt1 gene, which in turn shuts down its transcription. The transcriptional silencing of Dnmt1 may be responsible for the widespread passive hypomethylation of genomic DNA which we detect on the example of pericentromeric repeat sequences. Chromatin immunoprecipitation results show that in normal cells the Dnmt1 promoter is occupied by poly(ADP-ribosyl)ated Parp1, suggesting that PARylated Parp1 plays a role in protecting the promoter from methylation.In conclusion, the genome methylation pattern following PARG over-expression mirrors the pattern characteristic of cancer cells, supporting our idea that the right balance between Parp/Parg activities maintains the DNA methylation patterns in normal cells. The finding that in normal cells Parp1 and ADP-ribose polymers localize on the Dnmt1 promoter raises the possibility that PARylated Parp1 marks those sequences in the genome that must remain unmethylated and protects them from methylation, thus playing a role in the epigenetic regulation of gene expression

Nutritional Factors Modulating Alu Methylation inan Italian Sample from The Mark-Age StudyIncluding Offspring of Healthy Nonagenarians

Alu hypomethylation promotes genomic instability and is associated with aging and age-related diseases. Dietary factors affect global DNA methylation, leading to changes in genomic stability and gene expression with an impact on longevity and the risk of disease. This preliminary study aims to investigate the relationship between nutritional factors, such as circulating trace elements, lipids and antioxidants, and Alu methylation in elderly subjects and offspring of healthy nonagenarians. Alu DNA methylation was analyzed in sixty RASIG (randomly recruited age-stratified individuals from the general population) and thirty-two GO (GeHA offspring) enrolled in Italy in the framework of the MARK-AGE project. Factor analysis revealed a different clustering between Alu CpG1 and the other CpG sites. RASIG over 65 years showed lower Alu CpG1 methylation than those of GO subjects in the same age class. Moreover, Alu CpG1 methylation was associated with fruit and whole-grain bread consumption, LDL2-Cholesterol and plasma copper. The preserved Alu methylation status in GO, suggests Alu epigenetic changes as a potential marker of aging. Our preliminary investigation shows that Alu methylation may be affected by food rich in fibers and antioxidants, or circulating LDL subfractions and plasma copper