Cytosine Methyltransferases as Tumor Markers

Changes in DNA methylation patterns is a prominent characteristic of human tumors. Tumor cells display reduced levels of genomic DNA methylation and site-specific CpG island hypermethylation. Methylation of CpG dinucleotides is catalyzed by the enzyme family of DNA methyltransferases (DNMTs). In this review, the role of DNA methylation and DNMTs as key determinants of carcinogenesis is further elucidated. The chromatin modifying proteins that are known to interact with DNMTs are also described. Finally, the role of DNMTs as potential therapeutic targets is addressed

Distinct IL-1α-responsive enhancers promote acute and coordinated changes in chromatin topology in a hierarchical manner

How cytokine-driven changes in chromatin topology are converted into gene regulatory circuits during inflammation still remains unclear. Here, we show that interleukin (IL)-1α induces acute and widespread changes in chromatin accessibility via the TAK1 kinase and NF-κB at regions that are highly enriched for inflammatory disease-relevant SNPs. Two enhancers in the extended chemokine locus on human chromosome 4 regulate the IL-1α-inducible IL8 and CXCL1-3 genes. Both enhancers engage in dynamic spatial interactions with gene promoters in an IL-1α/TAK1-inducible manner. Microdeletions of p65-binding sites in either of the two enhancers impair NF-κB recruitment, suppress activation and biallelic transcription of the IL8/CXCL2 genes, and reshuffle higher-order chromatin interactions as judged by i4C interactome profiles. Notably, these findings support a dominant role of the IL8 “master” enhancer in the regulation of sustained IL-1α signaling, as well as for IL-8 and IL-6 secretion. CRISPR-guided transactivation of the IL8 locus or cross-TAD regulation by TNFα-responsive enhancers in a different model locus supports the existence of complex enhancer hierarchies in response to cytokine stimulation that prime and orchestrate proinflammatory chromatin responses downstream of NF-κB

Management of obstructive sleep apnea in Europe – A 10-year follow-up

Funding Information: Sleep medicine has been further established and recognized in the past 10 years. This is also shown by the fact that sleep-related diseases may receive a separate chapter in the new ICD-11 (International Classification of Diseases 11th Revision) [11]. However, the initial expansion in sleep laboratories and sleep centers seems to be over, at least in Europe, which stands in contradiction to the growing need. While sleep medical care still seems to be secured by the established structures, the gap between the increasing need and existing structures is still widening [ 12–14]. There is a lack of sleep medicine specialists, new outpatient structures, and new billing models with the sponsoring institutions. Approaches to solve these problems include the establishment and expansion of home sleep apnea testing (HSAT) [15] and telemedicine-based technologies in the diagnosis and treatment of OSA [16,17]. Telemedicine found its way into sleep medicine around 10 years ago [ 18–20]. One of the very first approaches as early as 1994 used a telephone circuit and a computer-controlled support system to improve OSA treatment by improving lifestyle through tele-guidance on nutrition and exercise [21]. Publisher Copyright: © 2022 The Authors Copyright © 2022 Elsevier B.V. All rights reserved.Objective: In 2010, a questionnaire-based study on obstructive sleep apnea (OSA) management in Europe identified differences regarding reimbursement, sleep specialist qualification, and titration procedures. Now, 10 years later, a follow-up study was conducted as part of the ESADA (European Sleep Apnea Database) network to explore the development of OSA management over time. Methods: The 2010 questionnaire including questions on sleep diagnostic, reimbursement, treatment, and certification was updated with questions on telemedicine and distributed to European Sleep Centers to reflect European OSA management practice. Results: 26 countries (36 sleep centers) participated, representing 20 ESADA and 6 non-ESADA countries. All 21 countries from the 2010 survey participated. In 2010, OSA diagnostic procedures were performed mainly by specialized physicians (86%), whereas now mainly by certified sleep specialists and specialized physicians (69%). Treatment and titration procedures are currently quite homogenous, with a strong trend towards more Autotitrating Positive Airway Pressure treatment (in hospital 73%, at home 62%). From 2010 to 2020, home sleep apnea testing use increased (76%–89%) and polysomnography as sole diagnostic procedure decreased (24%–12%). Availability of a sleep specialist qualification increased (52%–65%) as well as the number of certified polysomnography scorers (certified physicians: 36%–79%; certified technicians: 20%–62%). Telemedicine, not surveyed in 2010, is now in 2020 used in diagnostics (8%), treatment (50%), and follow-up (73%). Conclusion: In the past decade, formal qualification of sleep center personnel increased, OSA diagnostic and treatment procedures shifted towards a more automatic approach, and telemedicine became more prominent.Peer reviewe

Phylogenetic analysis of the eukaryotic RNA (cytosine-5)-methyltransferases

RNA (cytosine-5)-methyltransferases (RCMTs) have been characterized both in prokaryotic and eukaryotic organisms. The RCMT family, however, remains largely uncharacterized, as opposed to the family of DNA (cytosine-5)-methyltransferases which has been studied in depth. In the present study, an in silico identification of the putative 5-methylcytosine RNA-generating enzymes in the eukaryotic genomes was performed. A comprehensive phylogenetic analysis of the putative eukaryotic RCMT-related proteins has been performed in order to redefine subfamilies within the RCMT family. Five distinct eukaryotic subfamilies were identified, including the three already known (NOP2, NCL1 and YNL022c), one novel subfamily (RCMT9) and a fifth one which hitherto was considered to exist exclusively in prokaryotes (Fmu). The potential evolutionary relationships among the different eukaryotic RCMT subfamilies were also investigated. Furthermore, the results of this study add further support to a previous hypothesis that RCMTs represent evolutionary intermediates of RNA (uridine-5)-methyltransferases and DNA (cytosine-5)-methyltransferases. (C) 2008 Elsevier Inc. All rights reserved

Plant cytosine-5 DNA methyltransferases: Structure, function, and molecular evolution

A detailed analysis of the structure and function, along with evolutionary aspects, of the main plant cytosine-5 DNA methyltransferases (C5-MTases) is presented. The evolutionary relationships between the already known and four candidate plant C5-MTases identified in this work were investigated using the distance, maximum-parsimony, and maximum-likelihood approaches. The topologies of the trees were overall congruent: four monophyletic groups corresponding to the four plant C5-MTase families were clearly distinguished. In addition, sequence analyses of the plant C5-MTase target recognition domain sequences were performed and phylogenetic trees were reconstructed showing that there is good conservation among but not within the plant C5-MTase families. Furthermore, a conserved dipeptide that plays an important role in flipping the target base into the catalytic site of the C5-MTases was identified in all plant C5-MTases under study. (C) 2007 Elsevier Inc. All rights reserved

Unraveling microalgal molecular interactions using evolutionary and structural bioinformatics

Microalgae are unicellular microorganisms indispensible for environmental stability and life on earth, because they produce approximately half of the atmospheric oxygen, with simultaneously feeding on the harmful greenhouse gas carbon dioxide. Using gene fusion analysis, a series of five fusion/fission events was identified, that provided the basis for critical insights to their evolutionary history. Moreover, the three-dimensional structures of both the fused and the component proteins were predicted, allowing us to envisage putative protein-protein interactions that are invaluable for the efficient usage, handling and exploitation of microalgae. Collectively, our proposed approach on the five fusion/fission alga protein events contributes towards the expansion of the microalgae knowledgebase, bridging protein evolution of the ancient microalgal species and the rapidly evolving, modern, bioinformatics field. (C) 2013 Elsevier B.V. All rights reserved

3D molecular modeling and evolutionary study of the Trypanosoma brucei DNA Topoisomerase IB, as a new emerging pharmacological target

In the present study, an outline is proposed that may lead to specific drug design targeting of the Trypanosoma brucei DNA Topoisomerase IB. In this direction, an unequivocally specific platform was designed for the development of selective modulators, The designed platform is focused on the unique structural and catalytic features of the enzyme. Extensive phylogenetic analysis based on all available published genomes indicated a broad distribution of DNA topoisomerases across eukaryotic species and revealed structurally important amino acids which could be assigned as potentially strong contributors to the regulation of the mechanism of the T. brucei DNA Topoisomerase IB. Based on the above, we propose a comprehensive in silico 3D model for the structure of the T. brucei DNA Topoisomerase IB. Our approach provides an efficient intergraded platform with both evolutionary and structural insights for the rational design of pharmacophore models as well as novel modulators as the anti-T. brucei DNA Topoisomerase IB agents with therapeutic potential. (C) 2013 Published by Elsevier Inc