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Garagnani P.,University of Bologna | Garagnani P.,Applied Biomedical Research Center | Giuliani C.,University of Bologna | Pirazzini C.,University of Bologna | And 23 more authors.
Aging | Year: 2013

Genetic association studies of age-related, chronic human diseases often suffer from a lack of power to detect modest effects. Here we propose an alternative approach of including healthy centenarians as a more homogeneous and extreme control group. As a proof of principle we focused on type 2 diabetes (T2D) and assessed allelic/genotypic associations of 31 SNPs associated with T2D, diabetes complications and metabolic diseases and SNPs of genes relevant for telomere stability and age-related diseases. We hypothesized that the frequencies of risk variants are inversely correlated with decreasing health and longevity. We performed association analyses comparing diabetic patients and non-diabetic controls followed by association analyses with extreme phenotypic groups (T2D patients with complications and centenarians). Results drew attention to rs7903146 (TCF7L2 gene) that showed a constant increase in the frequencies of risk genotype (TT) from centenarians to diabetic patients who developed macro-complications and the strongest genotypic association was detected when diabetic patients were compared to centenarians (p_value = 9.066*10-7). We conclude that robust and biologically relevant associations can be obtained when extreme phenotypes, even with a small sample size, are compared. © Paolo Garagnani1et al.

Bacalini M.G.,University of Bologna | Bacalini M.G.,Personal Genomics S.r.l. | Boattini A.,University of Bologna | Gentilini D.,CNR Institute of Biomedical Technologies | And 20 more authors.
Aging | Year: 2015

Aging is characterized by a profound remodeling of the epigenetic architecture in terms of DNA methylation patterns. To date the most effective tool to study genome wide DNA methylation changes is Infinium HumanMethylation450 BeadChip (Infinium 450k). Despite the wealth of tools for Infinium 450k analysis, the identification of the most biologically relevant DNA methylation changes is still challenging. Here we propose an analytical pipeline to select differentially methylated regions (DMRs), tailored on microarray architecture, which is highly effective in highlighting biologically relevant results. The pipeline groups microarray probes on the basis of their localization respect to CpG islands and genic sequences and, depending on probes density, identifies DMRs through a single-probe or a regioncentric approach that considers the concomitant variation of multiple adjacent CpG probes. We successfully applied this analytical pipeline on 3 independent Infinium 450k datasets that investigated age-associated changes in blood DNA methylation. We provide a consensus list of genes that systematically vary in DNA methylation levels from 0 to 100 years and that have a potentially relevant role in the aging process. © Bacalini et al.

Bacalini M.G.,University of Bologna | Bacalini M.G.,Personal Genomics S.r.l. | Gentilini D.,CNR Institute of Biomedical Technologies | Boattini A.,University of Bologna | And 26 more authors.
Aging | Year: 2015

Down Syndrome (DS) is characterized by a wide spectrum of clinical signs, which include segmental premature aging of central nervous and immune systems. Although it is well established that the causative defect of DS is the trisomy of chromosome 21, the molecular bases of its phenotype are still largely unknown. We used the Infinium HumanMethylation450 BeadChip to investigate DNA methylation patterns in whole blood from 29 DS persons, using their relatives (mothers and unaffected siblings) as controls. This family-based model allowed us to monitor possible confounding effects on DNA methylation patterns deriving from genetic and environmental factors. Although differentially methylated regions (DMRs) displayed a genome-wide distribution, they were enriched on chromosome 21. DMRs mapped in genes involved in developmental functions, including embryonic development (HOXA family) and haematological (RUNX1 and EBF4) and neuronal (NCAM1) development. Moreover, genes involved in the regulation of chromatin structure (PRMD8, KDM2B, TET1) showed altered methylation. The data also showed that several pathways are affected in DS, including PI3K-Akt signaling. In conclusion, we identified an epigenetic signature of DS that sustains a link between developmental defects and disease phenotype, including segmental premature aging. © Bacalini et al.

Bacalini M.G.,University of Bologna | Bacalini M.G.,Personal Genomics S.r.l. | Pacilli A.,University of Bologna | Giuliani C.,University of Bologna | And 10 more authors.
BMC Cancer | Year: 2014

Background: There is a body of evidence that shows a link between tumorigenesis and ribosome biogenesis. The precursor of mature 18S, 28S and 5.8S ribosomal RNAs is transcribed from the ribosomal DNA gene (rDNA), which exists as 300-400 copies in the human diploid genome. Approximately one half of these copies are epigenetically silenced, but the exact role of epigenetic regulation on ribosome biogenesis is not completely understood. In this study we analyzed the methylation profiles of the rDNA promoter and of the 5' regions of 18S and 28S in breast cancer.Methods: We analyzed rDNA methylation in 68 breast cancer tissues of which the normal counterpart was partially available (45/68 samples) using the MassARRAY EpiTYPER assay, a sensitive and quantitative method with single base resolution.Results: We found that rDNA locus tended to be hypermethylated in tumor compared to matched normal breast tissues and that the DNA methylation level of several CpG units within the rDNA locus was associated to nuclear grade and to nucleolar size of tumor tissues. In addition we identified a subgroup of samples in which large nucleoli were associated with very limited or absent rDNA hypermethylation in tumor respect to matched normal tissue.Conclusions: In conclusion, we suggest that rDNA is an important target of epigenetic regulation in breast tumors and that rDNA methylation level is associated to nucleolar size. © 2014 Bacalini et al.; licensee BioMed Central Ltd.

Pirazzini C.,University of Bologna | Giuliani C.,University of Bologna | Bacalini M.G.,University of Bologna | Boattini A.,University of Bologna | And 9 more authors.
Aging | Year: 2012

Little is known about the impact of space (geography/ancestry) and time (age of the individuals) on DNA methylation variability in humans. We investigated DNA methylation of the imprinted IGF2/H19 locus in: i) a cohort of individuals homogeneous for age and gender (males with restricted age range: 30-50 years) belonging to four Italian districts representative of the major genetic clines, informative for the geographical dimension; ii) a cohort of monozygotic (MZ) and dizygotic (DZ) twins of different ages (age-range: 22-97 years), informative for the temporal dimension. DNA methylation of the analyzed regions displayed high levels of inter-individual variability that could not be ascribed to any geographical cline. In MZ twins we identified two IGF2/H19 regions where the intra-couple variations significantly increased after the age of 60 years. The analysis of twins' individual life histories suggests that the within twin pairs difference is likely the result of the aging process itself, as sharing a common environment for long periods had no effect on DNA methylation divergence. On the whole, the data here reported suggest that: i) aging more than population genetics is responsible for the inter-individual variability in DNA methylation patterns in humans; ii) DNA methylation variability appears to be highly region-specific. © Pirazzini et al.

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