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Current Research on Eukaryotic Dna Methyltransferases
Published in Isaac Bekhor, Carol J. Mirell, C. C. Liew, Progress in Nonhistone Protein Research, 1985
Jean-Numa Lapeyre, Mathuros Ruchirawat, Frederick F. Becker
DNase I is known to digest active gene region at a higher rate than bulk or inactive gene regions in nuclei or chromatin.104 DNase I preferentially attacks certain well-defined sites in chromatin (so-called DNase I-hypersensitive sites) that are generally upstream but also downstream from a sensitive domain.108 Kuo et al.56 analyzed the status of the DNase I sensitivity of Hha I methylatable sites in conalbumin and ovalbumin genes from active oviduct vs. inactive erythrocyte nuclei of the chick. Their results indicated that residual methylated sites (Hha I cleavage resistant sites) arose from cells whose chromatin contain DNase I insensitive and inactive genes. On the other hand, erythrocyte chromatin DNase I-insensitive regions contained unmethylated Hha I sites. In addition, Kuo et al. observed that hypersensitive sites at the 3’ end of the conalbumin gene were present in both tissue chromatins, although a greater number of Hpa II and Hha I sites are methylated in inactive erythrocyte chromatin regions than in oviduct. These findings suggest that there is no simple relation between methylation (at least in the Hha I type of site) and DNase I hypersensitivity. Since nucleosomes are assembled shortly after replication in addition to NHC protein deposition, it is unclear how chromosomal proteins may perpetrate or initiate new patterns of methylation in eukaryotic genomes.
Regulation of C-Reactive Protein, Haptoglobin, and Hemopexin Gene Expression
Published in Andrzej Mackiewicz, Irving Kushner, Heinz Baumann, Acute Phase Proteins, 2020
Dipak P. Ramji, Riccardo Cortese, Gennaro Ciliberto
DNase-I-hypersensitive sites (DHSs) reflect changes in the conformational structure of the chromatin in response to the interaction of regulatory trans-acting factors with their target sequences.55 In order to identify putative regions involved in the control of CRP expression, the DHSs within and adjacent to the CRP gene were mapped in both uninduced and induced transgenic mice.53 In uninduced liver, a constitutive and tissue-specific DHS was identified in the 3′ flanking sequence downstream from the polyadenylation site. This region is probably involved in developmental control of CRP expression, a conclusion supported by the observation that transgenic mice obtained with CRP constructs carrying a deletion of this DNA region do not express the transgene.53 The inflammatory stimulus LPS induces the appearance of three closely spaced, liver-specific DHSs. Two of these map around the CAP site and −250 bp, and the third one is located approximately 600 bp upstream.53 More recent work with transgenic mice has resulted in a better definition of the sequences involved in both liver-specific and inducible expression.56 Several segments of the original construct were tested either alone or in various combinations. The conclusion of this study is that correct regulation requires a cooperation of signals located in the immediate 5′ and 3′ flanking sequence of the gene (which includes the DHSs previously mapped), and a 2-kb region containing the CRP pseudogene,57 which is located 6 to 8 kb downstream from the CRP gene.56 The role of this last region is to ensure a consistently low background level of expression in noninduced mice and a high degree of inducibility.
Assessment of de novo copy-number variations in Italian patients with schizophrenia: Detection of putative mutations involving regulatory enhancer elements
Published in The World Journal of Biological Psychiatry, 2019
Giulio Piluso, Palmiero Monteleone, Silvana Galderisi, Teresa Giugliano, Alessandro Bertolino, Paola Rocca, Alessandro Rossi, Armida Mucci, Eugenio Aguglia, Ileana Andriola, Antonello Bellomo, Anna Comparelli, Francesco Gambi, Andrea Fagiolini, Carlo Marchesi, Rita Roncone, Emilio Sacchetti, Paolo Santonastaso, Alberto Siracusano, Paolo Stratta, Alfonso Tortorella, Luca Steardo, Paola Bucci, Vincenzo Nigro, Mario Maj
In this scenario, it has been postulated that genetic variants may appear de novo to increase the population risk for the disorder (Xu et al. 2011, 2012; Fromer et al. 2014). The analysis of de novo variants in schizophrenia has included not only CNVs but also single-nucleotide and small InsDel variants (Girard et al. 2011; Xu et al. 2011, 2012; Mulle et al. 2010, 2014). Specifically, rare de novo CNVs that disrupt genes involved in signalling and neurodevelopmental pathways as well as in synaptic plasticity have been associated to schizophrenia (Walsh et al. 2008; Kirov et al. 2012). Moreover, some lines of evidence have suggested that sequence variants or CNVs in non-coding regions of the human genome, as those occurring in cis-regulatory elements (CREs) such as promoters or enhancers, could contribute to a wide spectrum of psychiatric conditions, including schizophrenia (Visel et al. 2004; Walsh et al. 2008; International Schizophrenia Consortium 2008; Cooper et al. 2011; Malhotra et al. 2011; Xiao et al. 2017; Li and Weiberger 2017), very probably by altering transcriptional regulation in the brain (Roussos et al. 2014). A CRE is a non-coding DNA sequence regulating the spatiotemporal expression of target genes localised near or distant to the CRE itself. GWASs have identified many disease- and trait-associated non-coding genetic variants enriched in regulatory DNA marked by deoxyribonuclease I (DNase I) hypersensitive sites (DHSs), which lie within non-coding CREs (Maurano et al. 2012). These disease- and trait- associated variants can perturb transcription factor recognition sequences, the allelic chromatin state and regulatory networks (Won et al. 2016). Furthermore, Roussos et al. (2014) recently demonstrated that, in post-mortem human brain tissue, the risk variant of the L-type calcium channel (CACNA1C) gene, a well-established schizophrenia risk locus (Ripke et al. 2013), interacts physically with a distal enhancer and this is responsible for a reduced gene expression and transcriptional activity. Thus, it seems plausible that CRE mutations may contribute to the genetic risk for schizophrenia.