Dataset Information

Epigenetic Vulnerability of Insulator CTCF Motifs at Parkinson's Disease-Associated Genes in Response to Neurotoxicant Rotenone.

ABSTRACT: CCCTC-binding factor (CTCF) is a regulatory protein that binds DNA to control spatial organization and transcription. The sequence-specific binding of CTCF is variable and is impacted by nearby epigenetic patterns. It has been demonstrated that non-coding genetic variants cluster with CTCF sites in topological associating domains and thus can affect CTCF activity on gene expression. Therefore, environmental factors that alter epigenetic patterns at CTCF binding sites may dictate the interaction of non-coding genetic variants with regulatory proteins. To test this mechanism, we treated human cell line HEK293 with rotenone for 24 h and characterized its effect on global epigenetic patterns specifically at regulatory regions of Parkinson's disease (PD) risk loci. We used RNA sequencing to examine changes in global transcription and identified over 2000 differentially expressed genes (DEGs, >1.5-fold change, FDR < 0.05). Among these DEGs, 13 were identified as PD-associated genes according to Genome-wide association studies meta-data. We focused on eight genes that have non-coding risk variants and a prominent CTCF binding site. We analyzed methylation of a total of 165 CGs surrounding CTCF binding sites and detected differential methylation (|>1%|, q < 0.05) in 45 CGs at 7 PD-associated genes. Of these 45 CGs, 47% were hypomethylated and 53% were hypermethylated. Interestingly, 5 out of the 7 genes had correlated gene upregulation with CG hypermethylation at CTCF and gene downregulation with CG hypomethylation at CTCF. We also investigated active H3K27ac surrounding the same CTCF binding sites within these seven genes. We observed a significant increase in H3K27ac in four genes (FDR < 0.05). Three genes (PARK2, GPRIN3, FER) showed increased CTCF binding in response to rotenone. Our data indicate that rotenone alters regulatory regions of PD-associated genes through changes in epigenetic patterns, and these changes impact high-order chromatin organization to increase the influence of non-coding variants on genome integrity and cellular survival.

SUBMITTER: Freeman DM

PROVIDER: S-EPMC7381335 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Epigenetic Vulnerability of Insulator CTCF Motifs at Parkinson's Disease-Associated Genes in Response to Neurotoxicant Rotenone.

Freeman Dana M DM Wang Zhibin Z

Frontiers in genetics 20200707

CCCTC-binding factor (CTCF) is a regulatory protein that binds DNA to control spatial organization and transcription. The sequence-specific binding of CTCF is variable and is impacted by nearby epigenetic patterns. It has been demonstrated that non-coding genetic variants cluster with CTCF sites in topological associating domains and thus can affect CTCF activity on gene expression. Therefore, environmental factors that alter epigenetic patterns at CTCF binding sites may dictate the interaction ...[more]

PMID: 32774342

Similar Datasets

Project description:BackgroundAllele-specific DNA methylation (ASM) describes genomic loci that maintain CpG methylation at only one inherited allele rather than having coordinated methylation across both alleles. The most prominent of these regions are germline ASMs (gASMs) that control the expression of imprinted genes in a parent of origin-dependent manner and are associated with disease. However, our recent report reveals numerous ASMs at non-imprinted genes. These non-germline ASMs are dependent on DNA methyltransferase 1 (DNMT1) and strikingly show the feature of random, switchable monoallelic methylation patterns in the mouse genome. The significance of these ASMs to human health has not been explored. Due to their shared allelicity with gASMs, herein, we propose that non-traditional ASMs are sensitive to exposures in association with human disease.ResultsWe first explore their conservancy in the human genome. Our data show that our putative non-germline ASMs were in conserved regions of the human genome and located adjacent to genes vital for neuronal development and maturation. We next tested the hypothesized vulnerability of these regions by exposing human embryonic kidney cell HEK293 with the neurotoxicant rotenone for 24 h. Indeed,14 genes adjacent to our identified regions were differentially expressed from RNA-sequencing. We analyzed the base-resolution methylation patterns of the predicted non-germline ASMs at two neurological genes, HCN2 and NEFM, with potential to increase the risk of neurodegeneration. Both regions were significantly hypomethylated in response to rotenone.ConclusionsOur data indicate that non-germline ASMs seem conserved between mouse and human genomes, overlap important regulatory factor binding motifs, and regulate the expression of genes vital to neuronal function. These results support the notion that ASMs are sensitive to environmental factors such as rotenone and may alter the risk of neurological disease later in life by disrupting neuronal development.

Dataset Information

Epigenetic Vulnerability of Insulator CTCF Motifs at Parkinson's Disease-Associated Genes in Response to Neurotoxicant Rotenone.

Publications

Epigenetic Vulnerability of Insulator CTCF Motifs at Parkinson's Disease-Associated Genes in Response to Neurotoxicant Rotenone.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets