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Epigenetic Connections between the Gene Regulatory Network and Chromatin Dynamics

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

Deadline for manuscript submissions: closed (30 November 2020) | Viewed by 22900

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Special Issue Editor

Dr. Sari Pennings

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Guest Editor

Centre for Cardiovascular Science, Queen's Medical Research Institute, University of Edinburgh, Edinburgh EH16 4TJ, UK
Interests: chromatin; epigenetics; development

Special Issue Information

Dear Colleagues,

Cells in tissues have different phenotypes and functions determined by lineage-specific and signal-responsive gene expression patterns. Activation or repression of gene transcription is facilitated by epigenetic mechanisms controlling the accessibility of DNA in nuclear chromatin. Transcription factors and histone- and DNA-modifying enzymes cooperate in gene regulatory networks that act on individual genes or genomic domains in the nucleus and can maintain gene expression patterns through cell divisions. This Special Issue focuses on gene regulation mechanisms involving transcription factors, epigenetic modifying and chromatin remodelling complexes acting at specific genomic loci or altering chromosomal dynamics. A better understanding of how cell types and cell states are defined will advance further insight into cell differentiation and cell function in normal tissues and in disease.

Potential topics include, but are not limited to:
- Gene Regulatory Network
- Chromosome / chromatin dynamics
- 3D genome and nuclear architecture
- Epigenome and transcriptome

Dr. Sari Pennings
Guest Editor

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

epigenetics
chromatin
nucleosome
gene regulation
gene activation and repression
transcription
histone modification
DNA methylation
non-coding RNA
chromosome dynamics

Published Papers (7 papers)

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Research

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16 pages, 5699 KiB

Open AccessArticle

The Expression of the Cancer-Associated lncRNA Snhg15 Is Modulated by EphrinA5-Induced Signaling

by Daniel Pensold, Julia Gehrmann, Georg Pitschelatow, Asa Walberg, Kai Braunsteffer, Julia Reichard, Amin Ravaei, Jenice Linde, Angelika Lampert, Ivan G. Costa and Geraldine Zimmer-Bensch

Int. J. Mol. Sci. 2021, 22(3), 1332; https://doi.org/10.3390/ijms22031332 - 29 Jan 2021

Cited by 4 | Viewed by 3124

Abstract

The Eph receptor tyrosine kinases and their respective ephrin-ligands are an important family of membrane receptors, being involved in developmental processes such as proliferation, migration, and in the formation of brain cancer such as glioma. Intracellular signaling pathways, which are activated by Eph receptor signaling, are well characterized. In contrast, it is unknown so far whether ephrins modulate the expression of lncRNAs, which would enable the transduction of environmental stimuli into our genome through a great gene regulatory spectrum. Applying a combination of functional in vitro assays, RNA sequencing, and qPCR analysis, we found that the proliferation and migration promoting stimulation of mouse cerebellar granule cells (CB) with ephrinA5 diminishes the expression of the cancer-related lncRNA Snhg15. In a human medulloblastoma cell line (DAOY) ephrinA5 stimulation similarly reduced SNHG15 expression. Computational analysis identified triple-helix-mediated DNA-binding sites of Snhg15 in promoters of genes found up-regulated upon ephrinA5 stimulation and known to be involved in tumorigenic processes. Our findings propose a crucial role of Snhg15 downstream of ephrinA5-induced signaling in regulating gene transcription in the nucleus. These findings could be potentially relevant for the regulation of tumorigenic processes in the context of glioma. Full article

(This article belongs to the Special Issue Epigenetic Connections between the Gene Regulatory Network and Chromatin Dynamics)

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17 pages, 3168 KiB

Open AccessArticle

A DNA Sequence Based Polymer Model for Chromatin Folding

by Rui Zhou and Yi Qin Gao

Int. J. Mol. Sci. 2021, 22(3), 1328; https://doi.org/10.3390/ijms22031328 - 29 Jan 2021

Cited by 4 | Viewed by 2255

Abstract

The recent development of sequencing technology and imaging methods has provided an unprecedented understanding of the inter-phase chromatin folding in mammalian nuclei. It was found that chromatin folds into topological-associated domains (TADs) of hundreds of kilo base pairs (kbps), and is further divided into spatially segregated compartments (A and B). The compartment B tends to be located near to the periphery or the nuclear center and interacts with other domains of compartments B, while compartment A tends to be located between compartment B and interacts inside the domains. These spatial domains are found to highly correlate with the mosaic CpG island (CGI) density. High CGI density corresponds to compartments A and small TADs, and vice versa. The variation of contact probability as a function of sequential distance roughly follows a power-law decay. Different chromosomes tend to segregate to occupy different chromosome territories. A model that can integrate these properties at multiple length scales and match many aspects is highly desired. Here, we report a DNA-sequence based coarse-grained block copolymer model that considers different interactions between blocks of different CGI density, interactions of TAD formation, as well as interactions between chromatin and the nuclear envelope. This model captures the various single-chromosome properties and partially reproduces the formation of chromosome territories. Full article

(This article belongs to the Special Issue Epigenetic Connections between the Gene Regulatory Network and Chromatin Dynamics)

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17 pages, 6571 KiB

Open AccessArticle

High-Throughput Flow Cytometry Combined with Genetic Analysis Brings New Insights into the Understanding of Chromatin Regulation of Cellular Quiescence

by Yasaman Zahedi, Mickael Durand-Dubief and Karl Ekwall

Int. J. Mol. Sci. 2020, 21(23), 9022; https://doi.org/10.3390/ijms21239022 - 27 Nov 2020

Cited by 8 | Viewed by 3059

Abstract

Cellular quiescence is a reversible differentiation state when cells are changing the gene expression program to reduce metabolic functions and adapt to a new cellular environment. When fission yeast cells are deprived of nitrogen in the absence of any mating partner, cells can reversibly arrest in a differentiated G₀-like cellular state, called quiescence. This change is accompanied by a marked alteration of nuclear organization and a global reduction of transcription. Using high-throughput flow cytometry combined with genetic analysis, we describe the results of a comprehensive screen for genes encoding chromatin components and regulators that are required for the entry and the maintenance of cellular quiescence. We show that the histone acetylase and deacetylase complexes, SAGA and Rpd3, have key roles both for G₀ entry and survival during quiescence. We reveal a novel function for the Ino80 nucleosome remodeling complex in cellular quiescence. Finally, we demonstrate that components of the MRN complex, Rad3, the nonhomologous end-joining, and nucleotide excision DNA repair pathways are essential for viability in G_0. Full article

(This article belongs to the Special Issue Epigenetic Connections between the Gene Regulatory Network and Chromatin Dynamics)

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21 pages, 2444 KiB

Open AccessArticle

Epigenetics of Muscle- and Brain-Specific Expression of KLHL Family Genes

by Kenneth C. Ehrlich, Carl Baribault and Melanie Ehrlich

Int. J. Mol. Sci. 2020, 21(21), 8394; https://doi.org/10.3390/ijms21218394 - 09 Nov 2020

Cited by 15 | Viewed by 3380

Abstract

KLHL and the related KBTBD genes encode components of the Cullin-E3 ubiquitin ligase complex and typically target tissue-specific proteins for degradation, thereby affecting differentiation, homeostasis, metabolism, cell signaling, and the oxidative stress response. Despite their importance in cell function and disease (especially, KLHL40, KLHL41, KBTBD13, KEAP1, and ENC1), previous studies of epigenetic factors that affect transcription were predominantly limited to promoter DNA methylation. Using diverse tissue and cell culture whole-genome profiles, we examined 17 KLHL or KBTBD genes preferentially expressed in skeletal muscle or brain to identify tissue-specific enhancer and promoter chromatin, open chromatin (DNaseI hypersensitivity), and DNA hypomethylation. Sixteen of the 17 genes displayed muscle- or brain-specific enhancer chromatin in their gene bodies, and most exhibited specific intergenic enhancer chromatin as well. Seven genes were embedded in super-enhancers (particularly strong, tissue-specific clusters of enhancers). The enhancer chromatin regions typically displayed foci of DNA hypomethylation at peaks of open chromatin. In addition, we found evidence for an intragenic enhancer in one gene upregulating expression of its neighboring gene, specifically for KLHL40/HHATL and KLHL38/FBXO32 gene pairs. Many KLHL/KBTBD genes had tissue-specific promoter chromatin at their 5′ ends, but surprisingly, two (KBTBD11 and KLHL31) had constitutively unmethylated promoter chromatin in their 3′ exons that overlaps a retrotransposed KLHL gene. Our findings demonstrate the importance of expanding epigenetic analyses beyond the 5′ ends of genes in studies of normal and abnormal gene regulation. Full article

(This article belongs to the Special Issue Epigenetic Connections between the Gene Regulatory Network and Chromatin Dynamics)

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15 pages, 3950 KiB

Open AccessArticle

Alterations of Rice (Oryza sativa L.) DNA Methylation Patterns Associated with Gene Expression in Response to Rice Black Streaked Dwarf Virus

by Linying Li, Yuqing He, Xueying Zhang, Hehong Zhang, Zongtao Sun, Junmin Li and Gaojie Hong

Int. J. Mol. Sci. 2020, 21(16), 5753; https://doi.org/10.3390/ijms21165753 - 11 Aug 2020

Cited by 6 | Viewed by 2723

Abstract

Rice black-streaked dwarf virus (RBSDV) causes severe yield losses in rice (Oryza sativa L.) in China. Studies have shown that the mechanisms of DNA methylation-mediated plant defense against DNA viruses and RNA viruses are different. However, in rice its function in response to infection of RBSDV, a double-stranded RNA virus, remains unclear. In this study, high-throughput single-base resolution bisulfite sequencing (BS-Seq) was carried out to analyze the distribution pattern and characteristics of cytosine methylation in RBSDV-infected rice. Widespread differences were identified in CG and non-CG contexts between the RBSDV-infected and RBSDV-free rice. We identified a large number of differentially methylated regions (DMRs) along the genome of RBSDV-infected rice. Additionally, the transcriptome sequencing analysis obtained 1119 differentially expressed genes (DEGs). Correlation analysis of DMRs-related genes (DMGs) and DEGs filtered 102 genes with positive correlation and 71 genes with negative correlation between methylation level at promoter regions and gene expression. Key genes associated with maintaining DNA methylation in rice were analyzed by RT-qPCR and indicated that OsDMT702 might be responsible for the global increase of DNA methylation level in rice under RBSDV stress. Our results suggest important roles of rice DNA methylation in response to RBSDV and provide potential target genes for rice antiviral immunity. Full article

(This article belongs to the Special Issue Epigenetic Connections between the Gene Regulatory Network and Chromatin Dynamics)

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22 pages, 3656 KiB

Open AccessArticle

DNA Methylation Is Correlated with Gene Expression during Diapause Termination of Early Embryonic Development in the Silkworm (Bombyx mori)

by Bing Li, Pei Hu, Lin-Bao Zhu, Ling-Ling You, Hui-Hua Cao, Jie Wang, Shang-Zhi Zhang, Ming-Hui Liu, Shahzad Toufeeq, Shou-Jun Huang and Jia-Ping Xu

Int. J. Mol. Sci. 2020, 21(2), 671; https://doi.org/10.3390/ijms21020671 - 20 Jan 2020

Cited by 12 | Viewed by 4171

Abstract

DNA modification is a naturally occurring DNA modification in prokaryotic and eukaryotic organisms and is involved in several biological processes. Although genome-wide methylation has been studied in many insects, the understanding of global and genomic DNA methylation during insect early embryonic development, is lacking especially for insect diapause. In this study, we analyzed the relationship between DNA methylomes and transcriptomes in diapause-destined eggs compared to diapause-terminated eggs in the silkworm, Bombyx mori (B. mori). The results revealed that methylation was sparse in this species, as previously reported. Moreover, methylation levels in diapause-terminated eggs (HCl-treated) were 0.05% higher than in non-treated eggs, mainly due to the contribution of CG methylation sites. Methylation tends to occur in the coding sequences and promoter regions, especially at transcription initiation sites and short interspersed elements. Additionally, 364 methylome- and transcriptome-associated genes were identified, which showed significant differences in methylation and expression levels in diapause-destined eggs when compared with diapause-terminated eggs, and 74% of methylome and transcriptome associated genes showed both hypermethylation and elevated expression. Most importantly, Kyoto Encyclopaedia of Genes and Genomes (KEGG) analyses showed that methylation may be positively associated with Bombyx mori embryonic development, by regulating cell differentiation, metabolism, apoptosis pathways and phosphorylation. Through analyzing the G2/M phase-specific E3 ubiquitin-protein ligase (G2E3), we speculate that methylation may affect embryo diapause by regulating the cell cycle in Bombyx mori. These findings will help unravel potential linkages between DNA methylation and gene expression during early insect embryonic development and insect diapause. Full article

(This article belongs to the Special Issue Epigenetic Connections between the Gene Regulatory Network and Chromatin Dynamics)

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Review

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24 pages, 4634 KiB

Open AccessReview

Chromatin Manipulation and Editing: Challenges, New Technologies and Their Use in Plants

by Kateryna Fal, Denisa Tomkova, Gilles Vachon, Marie-Edith Chabouté, Alexandre Berr and Cristel C. Carles

Int. J. Mol. Sci. 2021, 22(2), 512; https://doi.org/10.3390/ijms22020512 - 06 Jan 2021

Cited by 6 | Viewed by 3499

Abstract

An ongoing challenge in functional epigenomics is to develop tools for precise manipulation of epigenetic marks. These tools would allow moving from correlation-based to causal-based findings, a necessary step to reach conclusions on mechanistic principles. In this review, we describe and discuss the advantages and limits of tools and technologies developed to impact epigenetic marks, and which could be employed to study their direct effect on nuclear and chromatin structure, on transcription, and their further genuine role in plant cell fate and development. On one hand, epigenome-wide approaches include drug inhibitors for chromatin modifiers or readers, nanobodies against histone marks or lines expressing modified histones or mutant chromatin effectors. On the other hand, locus-specific approaches consist in targeting precise regions on the chromatin, with engineered proteins able to modify epigenetic marks. Early systems use effectors in fusion with protein domains that recognize a specific DNA sequence (Zinc Finger or TALEs), while the more recent dCas9 approach operates through RNA-DNA interaction, thereby providing more flexibility and modularity for tool designs. Current developments of “second generation”, chimeric dCas9 systems, aiming at better targeting efficiency and modifier capacity have recently been tested in plants and provided promising results. Finally, recent proof-of-concept studies forecast even finer tools, such as inducible/switchable systems, that will allow temporal analyses of the molecular events that follow a change in a specific chromatin mark. Full article

(This article belongs to the Special Issue Epigenetic Connections between the Gene Regulatory Network and Chromatin Dynamics)

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