1,721,137 research outputs found
Regulation and Function of DNA and Histone Methylations
No full textCell type specification, transcription factor binding site selection and transcriptional regulation are specific processes that require a fine regulation that cannot be simply explained by the mere DNA sequence. Similarly, genome stability, damage response as well as genomic imprints and X-chromosome inactivation are all processes that involve an epigenetic level of regulation. This includes the activity of several enzymes that act in concert to "place" or "remove" specific modifications shaping cells epigenomes with posttranslational modifications of histone proteins and modifications of DNA cytosine residues. In this review, we discuss the role of histone and DNA methylation in regulating different cellular processes with a particular emphasis on transcriptional regulation and on the mechanistic insights behind different enzymatic activities with a perspective towards their implications in human diseases
Mapping the function of polycomb proteins
No full textPolycomb group (PcG) proteins are master regulators of proliferation and development that play essential roles in human pathologies including cancers. PcGs act as gatekeepers of cellular identity, maintaining repression of a multitude of target genes. However, these properties have only been recently uncovered thanks to technological advances, first of all chromatin immunoprecipitations (ChIP), that allowed a systematic characterization of the activity of these factors in an unbiased manner at a genome-wide level. Using PcG protein as example, this chapter introduces the readers to the use of chromatin analysis (ChIP assays and replication timing) and how to move these approaches to a level of genome-wide interpretation
Emerging roles for Polycomb proteins in cancer
No full textThe activities of the heterogeneous Polycomb (PcG) group of proteins ensure that the developmental processes of proliferation and cellular identity establishment are carried out correctly. PcG proteins assemble stable multiprotein complexes that, together with additional factors, maintain their target genes in a transcriptionally repressive state. The biochemical and functional features of PcG proteins have been extensively investigated over the years. Here we analyse the biochemical and mechanistic proprieties of PcG proteins with respect to recent advances that link the genetic alterations of PcG activity to cancer development
Locked Chromophores as CD and NMR Probes for the Helical Conformation of Tetraamidic Macrocycles
No full textA series of tetraamidic homochiral macrocycles have been built convergently upon the introduction in the covalent scaffold of two 1,1'-binaphthyl-2,2'-diol derivatives, joined by aromatic spacers of differing
shapes and rigidity (p-phenyl, 4,4'-biphenyl, 3,3'-biphenyl) through aromatic amide functionalities,
perfectly positioned to intramolecularly hydrogen bond the naphtholic oxygen acceptors of the
binaphthyl units, in order to effectively lock the central chromophores in spatial proximity. The
combination of several techniques, namely NMR and CD spectroscopies, and computational modeling,
allows for a clear depiction of the structure and conformation of the macrocycles in solution. In the
case of the shape “unstable” 3,3'-biphenyl spacer, the preferred conformation of a “wrapped” form in a
relatively polar (EtOH) solvent is clearly signalled by CD spectroscopy by analyzing the changes in the
shape of the induced CD signal deriving from the central, achiral chromophore absorption band. The
rigid, covalent scaffold in which the two central 3,3'-biphenyl spacers are embedded raises the energetic
barrier for the rotation around the aryl–aryl bonds of the spacers to a value (8.0 kcal mol-1) much
higher than the value calculated in the case of unlocked biphenyls
EpiMINE, a computational program for mining epigenomic data
Full text linkBackground: In epigenetic research, both the increasing ease of high-throughput sequencing and a greater interest in genome-wide studies have resulted in an exponential flooding of epigenetic-related data in public domain. This creates an opportunity for exploring data outside the limits of any specific query-centred study. Such data have to undergo standard primary analyses that are accessible with multiple well-stabilized programs. Further downstream analyses, such as genome-wide comparative, correlative and quantitative analyses, are critical in deciphering key biological features. However, these analyses are only accessible for computational researchers and completely lack platforms capable of handling, analysing and linking multiple interdisciplinary datasets with efficient analytical methods. Results: Here, we present EpiMINE, a program for mining epigenomic data. It is a user-friendly, stand-alone computational program designed to support multiple datasets, for performing genome-wide correlative and quantitative analysis of ChIP-seq and RNA-seq data. Using data available from the ENCODE project, we illustrated several features of EpiMINE through different biological scenarios to show how easy some known observations can be verified. These results highlight how these approaches can be helpful in identifying novel biological features. Conclusions: EpiMINE performs different kinds of genome-wide quantitative and correlative analyses, using ChIP-seq- and RNA-seq-related datasets. Its framework enables it to be used by both experimental and computational researchers. EpiMINE can be downloaded from https://sourceforge.net/projects/epimine/
Epigenetic methylations and their connections with metabolism
No full textMetabolic pathways play fundamental roles in several processes that regulate cell physiology and adaptation to environmental changes. Altered metabolic pathways predispose to several different pathologies ranging from diabetes to cancer. Specific transcriptional programs tightly regulate the enzymes involved in cell metabolism and dictate cell fate regulating the differentiation into specialized cell types that contribute to metabolic adaptation in higher organisms. For these reasons, it is of extreme importance to identify signaling pathways and transcription factors that positively and negatively regulate metabolism. Genomic organization allows a plethora of different strategies to regulate transcription. Importantly, large evidence suggests that the quality of diet and the caloric regimen can influence the epigenetic state of our genome and that certain metabolic pathways are also epigenetically controlled reveling a tight crosstalk between metabolism and epigenomes. Here we focus our attention on methylation-based epigenetic reactions, on how different metabolic pathways control these activities, and how these can influence metabolism. Altogether, the recent discoveries linking these apparent distant areas reveal that an exciting field of research is emerging
Epigenetic factors in cancer development : polycomb group proteins
No full textThe role of chromatin-modifying factors in cancer biology emerged exponentially in the last 10 years, and increased attention has been focused on Polycomb group (PcG) proteins and their enzymatic activities. PcG proteins are repressive chromatin modifiers required for proliferation and development. The frequent deregulation of PcG activities in human tumors has direct oncogenic effects and results, essential for cancer cell proliferation. Here we will review the recent findings regarding PcG proteins in prospective tumor development, focusing on the molecular mechanisms that deregulate PcG expression in different tumors, at the downstream pathways to PcG expression (that contribute to cancer development) and at the mechanisms that regulate PcG recruitment to specific targets. Finally, we will speculate on the benefit of PcG inhibition for cancer treatment, reviewing potential pharmacological strategies
The controversial role of the Polycomb group proteins in transcription and cancer : how much do we not understand Polycomb proteins?
No full textPolycomb group proteins (PcGs) are a large protein family that includes diverse biochemical features assembled together in two large multiprotein complexes. These complexes maintain gene transcriptional repression in a cell type specific manner by modifying the surrounding chromatin to control development, differentiation and cell proliferation. PcGs are also involved in several diseases. PcGs are often directly or indirectly implicated in cancer development for which they have been proposed as potential targets for cancer therapeutic strategies. However, in the last few years a series of discoveries about the basic properties of PcGs and the identification of specific genetic alterations affecting specific Polycomb proteins in different tumours have converged to challenge old dogmas about PcG biological and molecular functions. In this review, we analyse these new data in the context of the old knowledge, highlighting the controversies and providing new models of interpretation and ideas that will perhaps bring some order among apparently contradicting observations. Polycomb group proteins (PcGs) assemble two large complexes with different biochemical features ensuring gene transcriptional repression in a cell-type specific manner by modifying the surrounding chromatin. PcGs control development, differentiation, cell proliferation and are involved in cancer onset. This review analyzes new evidences challenging old dogmas about PcG functions, highlighting the controversies and providing new models to interpret PcG activities
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