Submit to IJMS Review for IJMS Propose a Special Issue

Journal Menu

Journal Browser

Modifications of Molecular Structure and Interactions in Epigenome 2.0

Print Special Issue Flyer
Special Issue Editors
Special Issue Information
Keywords
Published Papers

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Biology".

Deadline for manuscript submissions: closed (28 February 2022) | Viewed by 13185

Share This Special Issue

Special Issue Editors

Dr. Csaba Hetényi

E-Mail Website
Guest Editor

Department of Pharmacology and Pharmacotherapy, Medical School, University of Pécs, Szigeti út 12, 7624 Pécs, Hungary
Interests: pharmacoinformatics; chemical biology; structural biochemistry; bioinformatics; bioanalysis; protein; peptide; signaling; epigenetics; Alzheimer's disease; HIV
Special Issues, Collections and Topics in MDPI journals

Dr. Uko Maran

E-Mail Website
Guest Editor

Institute of Chemistry, University of Tartu, 14A Ravila Str., 50411 Tartu, Estonia
Interests: theoretical and computer chemistry; malaria drug development
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Beyond the regulatory mechanisms of classical genetics, epigenetics offers new answers to fundamental questions of life. including fertility, embryo development, and aging. The molecular machinery of epigenetic regulation has been correlated with various aspects of environmental pollution, psychological stress, physical activity, and nutrition. Public health issues, such as tobacco smoking or alcoholism, have also been investigated in the context of epigenetics. In the past few decades, the identification of epigenetic drug targets has become an emerging field. Beyond the classical genetics background of cancer, epigenetic abnormalities have been detected during the initiation and propagation of the disease. The pathophysiology of autoimmune and inflammatory diseases has also been associated with epigenetic alterations of immune and other cells.

Epigenetic regulation involves heritable changes in gene expression that occur independent of changes in the primary DNA sequence. Such changes in gene expression are coupled to the chromatin structure. Modifications of its components, like DNA methylation, covalent histone modifications, nucleosome positioning, histone variants, and miRNAs, adds up to combinatorial patterns collectively termed as epigenome. The regulatory machinery also involves numerous enzymes and other proteins interacting with chromatin components. The understanding and precise description of such molecular interactions is key to the mapping of the epigenome, and to the design of new molecules interfering with epigenetic diseases. The present Special Issue welcomes manuscripts on molecular interactions of epigenetic regulation, including new methodological approaches and applications of established techniques.

Dr. Csaba Hetényi
Dr. Uko Maran
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

molecular epigenetics
chemical epigenetics
cryo-electronmicroscopy
crystallography
NMR
structural bioinformatics
cheminformatics
molecular modeling
molecular dynamics
docking target selection
target validation
post-translational modification
PTM
covalent modification
methylation
acetylation
histone code
reader
writer
transferase
PHD finger
bromodomain
free energy
binding
isothermal titration calorimetry
surface plasmon resonance spectroscopy
peptide

Published Papers (5 papers)

Download All Papers

Research

Jump to: Review

16 pages, 2366 KiB

Open AccessArticle

The Structural Effects of Phosphorylation of Protein Arginine Methyltransferase 5 on Its Binding to Histone H4

by Rita Börzsei, Bayartsetseg Bayarsaikhan, Balázs Zoltán Zsidó, Beáta Lontay and Csaba Hetényi

Int. J. Mol. Sci. 2022, 23(19), 11316; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms231911316 - 26 Sep 2022

Viewed by 1835

Abstract

The protein arginine methyltransferase 5 (PRMT5) enzyme is responsible for arginine methylation on various proteins, including histone H4. PRMT5 is a promising drug target, playing a role in the pathomechanism of several diseases, especially in the progression of certain types of cancer. It was recently proved that the phosphorylation of PRMT5 on T80 residue increases its methyltransferase activity; furthermore, elevated levels of the enzyme were measured in the case of human hepatocellular carcinoma and other types of tumours. In this study, we constructed the complexes of the unmodified human PRMT5-methylosome protein 50 (MEP50) structure and its T80-phosphorylated variant in complex with the full-length histone H4 peptide. The full-length histone H4 was built in situ into the human PRMT5-MEP50 enzyme using experimental H4 fragments. Extensive molecular dynamic simulations and structure and energy analyses were performed for the complexed and apo protein partners, as well. Our results provided an atomic level explanation for two important experimental findings: (1) the increased methyltransferase activity of the phosphorylated PRMT5 when compared to the unmodified type; (2) the PRMT5 methylates only the free form of histone H4 not bound in the nucleosome. The atomic level complex structure H4-PRMT5-MEP50 will help the design of new inhibitors and in uncovering further structure–function relationships of PRMT enzymes. Full article

(This article belongs to the Special Issue Modifications of Molecular Structure and Interactions in Epigenome 2.0)

► Show Figures

Figure 1

25 pages, 5514 KiB

Open AccessArticle

Hypermethylation-Mediated Silencing of CIDEA, MAL and PCDH17 Tumour Suppressor Genes in Canine DLBCL: From Multi-Omics Analyses to Mechanistic Studies

by Eleonora Zorzan, Ramy Elgendy, Giorgia Guerra, Silvia Da Ros, Maria Elena Gelain, Federico Bonsembiante, Giulia Garaffo, Nicoletta Vitale, Roberto Piva, Laura Marconato, Luca Aresu, Mauro Dacasto and Mery Giantin

Int. J. Mol. Sci. 2022, 23(7), 4021; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23074021 - 05 Apr 2022

Cited by 3 | Viewed by 2394

Abstract

Gene expression is controlled by epigenetic deregulation, a hallmark of cancer. The DNA methylome of canine diffuse large B-cell lymphoma (cDLBCL), the most frequent malignancy of B-lymphocytes in dog, has recently been investigated, suggesting that aberrant hypermethylation of CpG loci is associated with gene silencing. Here, we used a multi-omics approach (DNA methylome, transcriptome and copy number variations) combined with functional in vitro assays, to identify putative tumour suppressor genes subjected to DNA methylation in cDLBCL. Using four cDLBCL primary cell cultures and CLBL-1 cells, we found that CiDEA, MAL and PCDH17, which were significantly suppressed in DLBCL samples, were hypermethylated and also responsive (at the DNA, mRNA and protein level) to pharmacological unmasking with hypomethylating drugs and histone deacetylase inhibitors. The regulatory mechanism underneath the methylation-dependent inhibition of those target genes expression was then investigated through luciferase and in vitro methylation assays. In the most responsive CpG-rich regions, an in silico analysis allowed the prediction of putative transcription factor binding sites influenced by DNA methylation. Interestingly, regulatory elements for AP2, MZF1, NF-kB, PAX5 and SP1 were commonly identified in all three genes. This study provides a foundation for characterisation and experimental validation of novel epigenetically-dysregulated pathways in cDLBCL. Full article

(This article belongs to the Special Issue Modifications of Molecular Structure and Interactions in Epigenome 2.0)

► Show Figures

Figure 1

23 pages, 6709 KiB

Open AccessArticle

Kynurenic Acid and Its Analog SZR104 Exhibit Strong Antiinflammatory Effects and Alter the Intracellular Distribution and Methylation Patterns of H3 Histones in Immunochallenged Microglia-Enriched Cultures of Newborn Rat Brains

by Melinda Szabo, Noémi Lajkó, Karolina Dulka, István Szatmári, Ferenc Fülöp, András Mihály, László Vécsei and Karoly Gulya

Int. J. Mol. Sci. 2022, 23(3), 1079; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23031079 - 19 Jan 2022

Cited by 6 | Viewed by 1998

Abstract

Kynurenic acid (KYNA) is implicated in antiinflammatory processes in the brain through several cellular and molecular targets, among which microglia-related mechanisms are of paramount importance. In this study, we describe the effects of KYNA and one of its analogs, the brain-penetrable SZR104 (N-(2-(dimethylamino)ethyl)-3-(morpholinomethyl)-4-hydroxyquinoline-2-carboxamide), on the intracellular distribution and methylation patterns of histone H3 in immunochallenged microglia cultures. Microglia-enriched secondary cultures made from newborn rat forebrains were immunochallenged with lipopolysaccharide (LPS). The protein levels of selected inflammatory markers C–X–C motif chemokine ligand 10 (CXCL10) and C–C motif chemokine receptor 1 (CCR1), histone H3, and posttranslational modifications of histone H3 lys methylation sites (H3K9me3 and H3K36me2, marks typically associated with opposite effects on gene expression) were analyzed using quantitative fluorescent immunocytochemistry and western blots in control or LPS-treated cultures with or without KYNA or SZR104. KYNA and SZR104 reduced levels of the inflammatory marker proteins CXCL10 and CCR1 after LPS-treatment. Moreover, KYNA and SZR104 favorably affected histone methylation patterns as H3K9me3 and H3K36me2 immunoreactivities, and histone H3 protein levels returned toward control values after LPS treatment. The cytoplasmic translocation of H3K9me3 from the nucleus indicated inflammatory distress, a process that could be inhibited by KYNA and SZR104. Thus, KYNA signaling and metabolism, and especially brain-penetrable KYNA analogs such as SZR104, could be key targets in the pathway that connects chromatin structure and epigenetic mechanisms with functional consequences that affect neuroinflammation and perhaps neurodegeneration. Full article

(This article belongs to the Special Issue Modifications of Molecular Structure and Interactions in Epigenome 2.0)

► Show Figures

Figure 1

16 pages, 2437 KiB

Open AccessArticle

Enriched Alternative Splicing in Islets of Diabetes-Susceptible Mice

by Ilka Wilhelmi, Alexander Neumann, Markus Jähnert, Meriem Ouni and Annette Schürmann

Int. J. Mol. Sci. 2021, 22(16), 8597; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22168597 - 10 Aug 2021

Cited by 6 | Viewed by 2707

Abstract

Dysfunctional islets of Langerhans are a hallmark of type 2 diabetes (T2D). We hypothesize that differences in islet gene expression alternative splicing which can contribute to altered protein function also participate in islet dysfunction. RNA sequencing (RNAseq) data from islets of obese diabetes-resistant and diabetes-susceptible mice were analyzed for alternative splicing and its putative genetic and epigenetic modulators. We focused on the expression levels of chromatin modifiers and SNPs in regulatory sequences. We identified alternative splicing events in islets of diabetes-susceptible mice amongst others in genes linked to insulin secretion, endocytosis or ubiquitin-mediated proteolysis pathways. The expression pattern of 54 histones and chromatin modifiers, which may modulate splicing, were markedly downregulated in islets of diabetic animals. Furthermore, diabetes-susceptible mice carry SNPs in RNA-binding protein motifs and in splice sites potentially responsible for alternative splicing events. They also exhibit a larger exon skipping rate, e.g., in the diabetes gene Abcc8, which might affect protein function. Expression of the neuronal splicing factor Srrm4 which mediates inclusion of microexons in mRNA transcripts was markedly lower in islets of diabetes-prone compared to diabetes-resistant mice, correlating with a preferential skipping of SRRM4 target exons. The repression of Srrm4 expression is presumably mediated via a higher expression of miR-326-3p and miR-3547-3p in islets of diabetic mice. Thus, our study suggests that an altered splicing pattern in islets of diabetes-susceptible mice may contribute to an elevated T2D risk. Full article

(This article belongs to the Special Issue Modifications of Molecular Structure and Interactions in Epigenome 2.0)

► Show Figures

Figure 1

Review

Jump to: Research

13 pages, 1153 KiB

Open AccessReview

Epigenetic Modulation of Vasopressin Expression in Health and Disease

by Bibiána Török, Csilla Lea Fazekas, Adrienn Szabó and Dóra Zelena

Int. J. Mol. Sci. 2021, 22(17), 9415; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22179415 - 30 Aug 2021

Cited by 3 | Viewed by 3296

Abstract

Vasopressin is a ubiquitous molecule playing an important role in a wide range of physiological processes thereby implicated in the pathomechanism of many disorders. Its effect is well characterized through V2 receptors, which regulates the water resorption in kidney, while its vasoconstrictory effect through V1a receptor also received a lot of attention in the maintenance of blood pressure during shock. However, the most striking is its central effect both through the V1b receptors in stress-axis regulation as well as through V1a receptors regulating many aspects of our behavior (e.g., social behavior, learning and memory). Vasopressin has been implicated in the development of depression, due to its connection with chronic stress, as well as schizophrenia because of its involvement in social interactions and memory processes. Epigenetic changes may also play a role in the development of these disorders. The possible mechanism includes DNA methylation, histone modification and/or micro RNAs, and these possible regulations will be in the focus of our present review. Full article

(This article belongs to the Special Issue Modifications of Molecular Structure and Interactions in Epigenome 2.0)

► Show Figures