The Progeny of Arabidopsis thaliana Plants Exposed to Salt Exhibit Changes in DNA Methylation, Histone Modifications and Gene Expression

Chromatin-modifying enzymes mediate DNA methylation and histone modifications on recruitment to specific target gene loci in response to various stimuli. The key enzymes that regulate chromatin accessibility for maintenance of modifications in DNA and histones, and for modulation of gene expression patterns in response to cigarette smoke (CS), are not known. We hypothesize that CS exposure alters the gene expression patterns of chromatin-modifying enzymes, which then affects multiple downstream pathways involved in the response to CS. We have, therefore, analyzed chromatin-modifying enzyme profiles and validated by quantitative real-time PCR (qPCR). We also performed immunoblot analysis of targeted histone marks in C57BL/6J mice exposed to acute and subchronic CS, and of lungs from nonsmokers, smokers, and patients with chronic obstructive pulmonary disease (COPD). We found a significant increase in expression of several chromatin modification enzymes, including DNA methyltransferases, histone acetyltransferases, histone methyltransferases, and SET domain proteins, histone kinases, and ubiquitinases. Our qPCR validation data revealed a significant downregulation of Dnmt1, Dnmt3a, Dnmt3b, Hdac2, Hdac4, Hat1, Prmt1, and Aurkb. We identified targeted chromatin histone marks (H3K56ac and H4K12ac), which are induced by CS. Thus CS-induced genotoxic stress differentially affects the expression of epigenetic modulators that regulate transcription of target genes via DNA methylation and site-specific histone modifications. This may have implications in devising epigenetic-based therapies for COPD and lung cancer.

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The COP9 signalosome influences the epigenetic landscape of Arabidopsis thaliana

Bioinformatics ◽

10.1093/bioinformatics/bty1053 ◽

2018 ◽

Vol 35 (16) ◽

pp. 2718-2723 ◽

Cited By ~ 3

Author(s):

Tamir Tuller ◽

Alon Diament ◽

Avital Yahalom ◽

Assaf Zemach ◽

Shimshi Atar ◽

...

Keyword(s):

Gene Expression ◽

Dna Methylation ◽

Arabidopsis Thaliana ◽

Gene Expression Regulation ◽

Developmental Pathways ◽

Cop9 Signalosome ◽

Supplementary Information ◽

Loss Of Function ◽

Genome Wide ◽

High Level

Abstract Motivation The COP9 signalosome is a highly conserved multi-protein complex consisting of eight subunits, which influences key developmental pathways through its regulation of protein stability and transcription. In Arabidopsis thaliana, mutations in the COP9 signalosome exhibit a number of diverse pleiotropic phenotypes. Total or partial loss of COP9 signalosome function in Arabidopsis leads to misregulation of a number of genes involved in DNA methylation, suggesting that part of the pleiotropic phenotype is due to global effects on DNA methylation. Results We determined and analyzed the methylomes and transcriptomes of both partial- and total-loss-of-function Arabidopsis mutants of the COP9 signalosome. Our results support the hypothesis that the COP9 signalosome has a global genome-wide effect on methylation and that this effect is at least partially encoded in the DNA. Our analyses suggest that COP9 signalosome-dependent methylation is related to gene expression regulation in various ways. Differentially methylated regions tend to be closer in the 3D conformation of the genome to differentially expressed genes. These results suggest that the COP9 signalosome has a more comprehensive effect on gene expression than thought before, and this is partially related to regulation of methylation. The high level of COP9 signalosome conservation among eukaryotes may also suggest that COP9 signalosome regulates methylation not only in plants but also in other eukaryotes, including humans. Supplementary information Supplementary data are available at Bioinformatics online.

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Epigenetic Variation Analysis Leads to Biomarker Discovery in Gastric Adenocarcinoma

Frontiers in Genetics ◽

10.3389/fgene.2020.551787 ◽

2020 ◽

Vol 11 ◽

Author(s):

Yan Zhang ◽

Dianjing Guo

Keyword(s):

Gene Expression ◽

Gastric Cancer ◽

Dna Methylation ◽

Gastric Adenocarcinoma ◽

Histone Modifications ◽

Biomarker Discovery ◽

Cancer Genome ◽

The Cancer Genome Atlas ◽

Integrated Analysis ◽

Epigenetic Variation

As one of the most common malignant tumors worldwide, gastric adenocarcinoma (GC) and its prognosis are still poorly understood. Various genetic and epigenetic factors have been indicated in GC carcinogenesis. However, a comprehensive and in-depth investigation of epigenetic alteration in gastric cancer is still missing. In this study, we systematically investigated some key epigenetic features in GC, including DNA methylation and five core histone modifications. Data from The Cancer Genome Atlas Program and other studies (Gene Expression Omnibus) were collected, analyzed, and validated with multivariate statistical analysis methods. The landscape of epi-modifications in gastric cancer was described. Chromatin state transition analysis showed a histone marker shift in gastric cancer genome by employing a Hidden-Markov-Model based approach, indicated that histone marks tend to label different sets of genes in GC compared to control. An additive effect of these epigenetic marks was observed by integrated analysis with gene expression data, suggesting epigenetic modifications may cooperatively regulate gene expression. However, the effect of DNA methylation was found more significant without the presence of the five histone modifications in our study. By constructing a PPI network, key genes to distinguish GC from normal samples were identified, and distinct patterns of oncogenic pathways in GC were revealed. Some of these genes can also serve as potential biomarkers to classify various GC molecular subtypes. Our results provide important insights into the epigenetic regulation in gastric cancer and other cancers in general. This study describes the aberrant epigenetic variation pattern in GC and provides potential direction for epigenetic biomarker discovery.

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Gestational Choline Supplementation Normalized Fetal Alcohol-Induced Alterations in Histone Modifications, DNA Methylation, and Proopiomelanocortin (POMC) Gene Expression in β-Endorphin-Producing POMC Neurons of the Hypothalamus

Alcoholism Clinical and Experimental Research ◽

10.1111/acer.12082 ◽

2013 ◽

Vol 37 (7) ◽

pp. 1133-1142 ◽

Cited By ~ 95

Author(s):

Rola A. Bekdash ◽

Changqing Zhang ◽

Dipak K. Sarkar

Keyword(s):

Gene Expression ◽

Dna Methylation ◽

Histone Modifications ◽

Fetal Alcohol ◽

Pomc Gene

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Epigenomics in an extraterrestrial environment: organ-specific alteration of DNA methylation and gene expression elicited by spaceflight in Arabidopsis thaliana

BMC Genomics ◽

10.1186/s12864-019-5554-z ◽

2019 ◽

Vol 20 (1) ◽

Cited By ~ 7

Author(s):

Mingqi Zhou ◽

Natasha J. Sng ◽

Collin E. LeFrois ◽

Anna-Lisa Paul ◽

Robert J. Ferl

Keyword(s):

Gene Expression ◽

Dna Methylation ◽

Arabidopsis Thaliana ◽

Organ Specific ◽

Extraterrestrial Environment ◽

Specific Alteration

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The Use of Natural Products of Epigenetic Modulators in Anti-Cancer Drug Studies

Proceedings ◽

10.3390/proceedings2019040041 ◽

2019 ◽

Vol 40 (1) ◽

pp. 41

Author(s):

Demokan

Keyword(s):

Gene Expression ◽

Dna Methylation ◽

Natural Products ◽

Cancer Treatment ◽

Tumor Cells ◽

Histone Modifications ◽

Regulation Of Gene Expression ◽

Epigenetic Mechanisms ◽

Expression Of Genes ◽

Anti Cancer

The natural products obtained from plants, bacteria, fungi and marine have been used in the treatment of human diseases throughout the centuries. These compounds of them also interfere with the expression of genes by influencing epigenetic mechanisms. Recent researches showed significant outcomes suggesting that epigenetic silencing of the main regulatory genesis a sign of cancer onset and its progression. Epigenetic mechanisms that regulate expression of genes without mutation in the DNA are carried through DNA methylation, histone modification, chromatin remodeling and RNA interference. DNA methylation observed in the promoter regions of genes and prevents binding of the transcription factors by suppressing gene expression or by altering the nucleosome package of DNA, and may also directly inhibit transcription. Plant based products, such as curcumin, flavonoids, genistein, have been shown to exhibit cytostatic and apoptotic activities by influencing DNA methylation-based gene expression regulation in tumor cells. Additionally, natural products such as sulforaphane, retinoic acid, cucurbitacin B, casein Q, parthenolide, folate, cobalamin, pyridoxine and methionine also are used as anti-cancer agents based on DNA methylation. On the other hand, microRNAs (miRNAs) play a particular role in the epigenetic regulation of gene expression in post-transcription and post-translation processes. Quercetin, tryptolide, and honokiol are the natural compounds used in miRNA based agents. Histone modifications, which also affect the chromatin structure, play an important role in the initiation and progression of carcinogenesis as well as regulation of gene expression. As expected particular inhibitors of histone acetyltransferases (HATs) and histone deacetylase (HDAC) enzymes which are responsible of histone modifications have been developed for epigenetic intervention in cancer treatment. Numerous natural compounds are known to affect histone-modifying enzymes; such as romidepsin, epigallocatechingallate (EGCG), daidzein, sulphorafane, glucoraphanin, parthenolide, triptolide, sinapinic acid. Natural epigenetic modulators developed for epigenetic mechanisms enable the destruction of apoptotic, necrotic or autophagic pathways of tumor cells. Beside epigenetic mechanisms, these products exert their effects through influencing the cell cycle, DNA repair, and epigenetic mechanisms which modulate gene expression. More extensive in vitro and in vivo studies are required to investigate the effect of natural product-based epigenetic agents which seems to be very promising for future cancer treatment approaches.

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KRAB-Induced Heterochromatin Effectively Silences PLOD2 Gene Expression in Somatic Cells and Is Resilient to TGFβ1 Activation

International Journal of Molecular Sciences ◽

10.3390/ijms21103634 ◽

2020 ◽

Vol 21 (10) ◽

pp. 3634

Author(s):

Rutger A. F. Gjaltema ◽

Désirée Goubert ◽

Christian Huisman ◽

Consuelo del Pilar García Tobilla ◽

Mihály Koncz ◽

...

Keyword(s):

Gene Expression ◽

Dna Methylation ◽

Histone Modifications ◽

Mammalian Cells ◽

Dna Methyltransferase ◽

De Novo ◽

Context Dependency ◽

Dependent Manner ◽

In Vivo Models ◽

Epigenetic Editing

Epigenetic editing, an emerging technique used for the modulation of gene expression in mammalian cells, is a promising strategy to correct disease-related gene expression. Although epigenetic reprogramming results in sustained transcriptional modulation in several in vivo models, further studies are needed to develop this approach into a straightforward technology for effective and specific interventions. Important goals of current research efforts are understanding the context-dependency of successful epigenetic editing and finding the most effective epigenetic effector(s) for specific tasks. Here we tested whether the fibrosis- and cancer-associated PLOD2 gene can be repressed by the DNA methyltransferase M.SssI, or by the non-catalytic Krüppel associated box (KRAB) repressor directed to the PLOD2 promoter via zinc finger- or CRISPR-dCas9-mediated targeting. M.SssI fusions induced de novo DNA methylation, changed histone modifications in a context-dependent manner, and led to 50%–70% reduction in PLOD2 expression in fibrotic fibroblasts and in MDA-MB-231 cancer cells. Targeting KRAB to PLOD2 resulted in the deposition of repressive histone modifications without DNA methylation and in almost complete PLOD2 silencing. Interestingly, both long-term TGFβ1-induced, as well as unstimulated PLOD2 expression, was completely repressed by KRAB, while M.SssI only prevented the TGFβ1-induced PLOD2 expression. Targeting transiently expressed dCas9-KRAB resulted in sustained PLOD2 repression in HEK293T and MCF-7 cells. Together, these findings point to KRAB outperforming DNA methylation as a small potent targeting epigenetic effector for silencing TGFβ1-induced and uninduced PLOD2 expression.

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Characterization of histone modifications associated with DNA damage repair genes upon exposure to gamma rays in Arabidopsis seedlings

Journal of Radiation Research ◽

10.1093/jrr/rrw077 ◽

2016 ◽

Vol 57 (6) ◽

pp. 646-654 ◽

Cited By ~ 9

Author(s):

Suvendu Mondal ◽

Young Sam Go ◽

Seung Sik Lee ◽

Byung Yeoup Chung ◽

Jin-Hong Kim

Keyword(s):

Gene Expression ◽

Dna Methylation ◽

Gamma Irradiation ◽

Histone Modifications ◽

Gamma Rays ◽

Regulation Of Gene Expression ◽

Chromatin Modification ◽

Histone H3 ◽

Marker Genes ◽

Transcription Start Sites

Abstract Dynamic histone modifications play an important role in controlling gene expression in response to various environmental cues. This mechanism of regulation of gene expression is important for sessile organisms, like land plants. We have previously reported consistent upregulation of various marker genes in response to gamma rays at various post-irradiation times. In the present study, we performed various chromatin modification analyses at selected loci using the standard chromatin immunoprecipitation procedure, and demonstrate that upregulation of these genes is associated with histone H3 lysine 4 tri-methylation (H3K4me3) at the gene body or transcription start sites of these loci. Further, at specific AtAgo2 loci, both H3K4me3 and histone H3 lysine 9 acetylation (H3K9ac) are important in controlling gene expression in response to gamma irradiation. There was no change in DNA methylation in these selected loci. We conclude that specific histone modification such as H3K4me3 and H3K9ac may be more important in activating gene expression in these selected loci in response to gamma irradiation than a change in DNA methylation.

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