ADP-ribose polymer depletion leads to nuclear Ctcf re-localization and chromatin rearrangement

Guastafierro, Tiziana; Catizone, Angela; Calabrese, R.; Zampieri, Michele; Martella, Oliviano; Bacalini, Maria Giulia; Reale, Anna; Girolamo, Maria Di; Miccheli, Margherita; Farrar, Dawn; Klenova, Elena; Ciccarone, Fabio; Caiafa, Paola

doi:10.1042/bj20121429

Cited by 27 publications

(15 citation statements)

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“…Previous studies have shown that CTCF and PARP-1 together, protect certain genomic regions from acquiring repressive epigenetic marks 42 , 43 . Oxidative stress, a common effect of arsenic exposure, disrupts the CTCF/PARP-1 interaction and may lead to increases in DNA methylation and other repressive epigenetic marks at the corresponding genomic loci 44 , 45 . Therefore, disruption of CTCF/PARP-1 insulator elements by arsenical induced ROS is one possible explanation of how H3K9me3 could spread from the 3′UTR of ZNF genes to the promoter regions, but future studies will have to show whether this hypothesis holds any merit.…”

Section: Discussionmentioning

confidence: 99%

Coordinate H3K9 and DNA methylation silencing of ZNFs in toxicant-induced malignant transformation

Severson¹,

Tokar²,

Vrba³

et al. 2013

Epigenetics

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Genome-wide disruption of the epigenetic code is a hallmark of malignancy that encompasses many distinct, highly interactive modifications. Delineating the aberrant epigenome produced during toxicant-mediated malignant transformation will help identify the underlying epigenetic drivers of environmental toxicant-induced carcinogenesis. Gene promoter DNA methylation and gene expression profiling of arsenite-transformed prostate epithelial cells showed a negative correlation between gene expression changes and DNA methylation changes; however, less than 10% of the genes with increased promoter methylation were downregulated. Studies described herein confirm that a majority of the DNA hypermethylation events occur at H3K27me3 marked genes that were already transcriptionally repressed. In contrast to aberrant DNA methylation targeting H3K27me3 pre-marked silent genes, we found that actively expressed C2H2 zinc finger genes (ZNFs) marked with H3K9me3 on their 3′ ends, were the favored targets of DNA methylation linked gene silencing. DNA methylation coupled, H3K9me3 mediated gene silencing of ZNF genes was widespread, occurring at individual ZNF genes on multiple chromosomes and across ZNF gene family clusters. At ZNF gene promoters, H3K9me3 and DNA hypermethylation replaced H3K4me3, resulting in a widespread downregulation of ZNF gene expression, which accounted for 8% of all the downregulated genes in the arsenical-transformed cells. In summary, these studies associate toxicant exposure with widespread silencing of ZNF genes by DNA hypermethylation-linked H3K9me3 spreading, further implicating epigenetic dysfunction as a driver of toxicant associated carcinogenesis.

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Section: Discussionmentioning

confidence: 99%

Coordinate H3K9 and DNA methylation silencing of ZNFs in toxicant-induced malignant transformation

Severson¹,

Tokar²,

Vrba³

et al. 2013

Epigenetics

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show abstract

“…It was suggested that interaction with some RNAs can increase the CTCF ability to form multimeric complexes [63] or to reduce the stability of CTCF binding to DNA [11]. The CTCF activity is also regulated by various posttranslational modifications: poly(ADP)-ribosylation [65], phosphorylation [66], and sumoylation [67]. …”

Section: Transcription Factors Containing Only a Single Cluster Of C2mentioning

confidence: 99%

C2H2 Zinc Finger Proteins: The Largest but Poorly Explored Family of Higher Eukaryotic Transcription Factors

et al. 2017

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The emergence of whole-genome assays has initiated numerous genome-wide studies of transcription factor localizations at genomic regulatory elements (enhancers, promoters, silencers, and insulators), as well as facilitated the uncovering of some of the key principles of chromosomal organization. However, the proteins involved in the formation and maintenance of the chromosomal architecture and the organization of regulatory domains remain insufficiently studied. This review attempts to collate the available data on the abundant but still poorly understood family of proteins with clusters of the C2H2 zinc finger domains. One of the best known proteins of this family is a well conserved protein known as CTCF, which plays a key role in the establishment of the chromosomal architecture in vertebrates. The distinctive features of C2H2 zinc finger proteins include strong and specific binding to a long and unique DNA recognition target sequence and rapid expansion within various animal taxa during evolution. The reviewed data support a proposed model according to which many of the C2H2 proteins have functions that are similar to those of the CTCF in the organization of the chromatin architecture.

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“…Any chemically-induced deficiency of PARP activity would be expected to result in de-repressed DNMT1 and hypermethylation as well as compromised CTCF binding to DNA targets. These predictions were realized in a subsequent study in which depletion of poly(ADP–ribose) caused CTCF to lose it diffuse nuclear localization and accumulate at the nuclear periphery due to being blocked from nuclear entry [250]. Also a generalized genomic hypermethylation and an increased H3K9me3 repressive chromatin content were measured as a consequence of poly(ADP-ribose) depletion, reinforcing the idea that the high degree of interaction between CTCF and poly(ADP–ribosyl)ation is important for chromatin organization and DNA methylation patterns.…”

Section: Ctcf and Control Of Epigenetic Modifications In Tsgsmentioning

confidence: 99%

A Tox21 Approach to Altered Epigenetic Landscapes: Assessing Epigenetic Toxicity Pathways Leading to Altered Gene Expression and Oncogenic Transformation In Vitro

Parfett

Desaulniers

2017

IJMS

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An emerging vision for toxicity testing in the 21st century foresees in vitro assays assuming the leading role in testing for chemical hazards, including testing for carcinogenicity. Toxicity will be determined by monitoring key steps in functionally validated molecular pathways, using tests designed to reveal chemically-induced perturbations that lead to adverse phenotypic endpoints in cultured human cells. Risk assessments would subsequently be derived from the causal in vitro endpoints and concentration vs. effect data extrapolated to human in vivo concentrations. Much direct experimental evidence now shows that disruption of epigenetic processes by chemicals is a carcinogenic mode of action that leads to altered gene functions playing causal roles in cancer initiation and progression. In assessing chemical safety, it would therefore be advantageous to consider an emerging class of carcinogens, the epigenotoxicants, with the ability to change chromatin and/or DNA marks by direct or indirect effects on the activities of enzymes (writers, erasers/editors, remodelers and readers) that convey the epigenetic information. Evidence is reviewed supporting a strategy for in vitro hazard identification of carcinogens that induce toxicity through disturbance of functional epigenetic pathways in human somatic cells, leading to inactivated tumour suppressor genes and carcinogenesis. In the context of human cell transformation models, these in vitro pathway measurements ensure high biological relevance to the apical endpoint of cancer. Four causal mechanisms participating in pathways to persistent epigenetic gene silencing were considered: covalent histone modification, nucleosome remodeling, non-coding RNA interaction and DNA methylation. Within these four interacting mechanisms, 25 epigenetic toxicity pathway components (SET1, MLL1, KDM5, G9A, SUV39H1, SETDB1, EZH2, JMJD3, CBX7, CBX8, BMI, SUZ12, HP1, MPP8, DNMT1, DNMT3A, DNMT3B, TET1, MeCP2, SETDB2, BAZ2A, UHRF1, CTCF, HOTAIR and ANRIL) were found to have experimental evidence showing that functional perturbations played “driver” roles in human cellular transformation. Measurement of epigenotoxicants presents challenges for short-term carcinogenicity testing, especially in the high-throughput modes emphasized in the Tox21 chemicals testing approach. There is need to develop and validate in vitro tests to detect both, locus-specific, and genome-wide, epigenetic alterations with causal links to oncogenic cellular phenotypes. Some recent examples of cell-based high throughput chemical screening assays are presented that have been applied or have shown potential for application to epigenetic endpoints.

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ADP-ribose polymer depletion leads to nuclear Ctcf re-localization and chromatin rearrangement

Cited by 27 publications

References 50 publications

Coordinate H3K9 and DNA methylation silencing of ZNFs in toxicant-induced malignant transformation

Coordinate H3K9 and DNA methylation silencing of ZNFs in toxicant-induced malignant transformation

C2H2 Zinc Finger Proteins: The Largest but Poorly Explored Family of Higher Eukaryotic Transcription Factors

A Tox21 Approach to Altered Epigenetic Landscapes: Assessing Epigenetic Toxicity Pathways Leading to Altered Gene Expression and Oncogenic Transformation In Vitro

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