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The conserved DNMT1-dependent methylation regions in human cells are vulnerable to neurotoxicant rotenone exposure

BACKGROUND: Allele-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 g...

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Autores principales: Freeman, Dana M., Lou, Dan, Li, Yanqiang, Martos, Suzanne N., Wang, Zhibin
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7076959/
https://www.ncbi.nlm.nih.gov/pubmed/32178731
http://dx.doi.org/10.1186/s13072-020-00338-8
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author Freeman, Dana M.
Lou, Dan
Li, Yanqiang
Martos, Suzanne N.
Wang, Zhibin
author_facet Freeman, Dana M.
Lou, Dan
Li, Yanqiang
Martos, Suzanne N.
Wang, Zhibin
author_sort Freeman, Dana M.
collection PubMed
description BACKGROUND: Allele-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. RESULTS: We 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. CONCLUSIONS: Our 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.
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spelling pubmed-70769592020-03-18 The conserved DNMT1-dependent methylation regions in human cells are vulnerable to neurotoxicant rotenone exposure Freeman, Dana M. Lou, Dan Li, Yanqiang Martos, Suzanne N. Wang, Zhibin Epigenetics Chromatin Research BACKGROUND: Allele-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. RESULTS: We 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. CONCLUSIONS: Our 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. BioMed Central 2020-03-16 /pmc/articles/PMC7076959/ /pubmed/32178731 http://dx.doi.org/10.1186/s13072-020-00338-8 Text en © The Author(s) 2020 Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
spellingShingle Research
Freeman, Dana M.
Lou, Dan
Li, Yanqiang
Martos, Suzanne N.
Wang, Zhibin
The conserved DNMT1-dependent methylation regions in human cells are vulnerable to neurotoxicant rotenone exposure
title The conserved DNMT1-dependent methylation regions in human cells are vulnerable to neurotoxicant rotenone exposure
title_full The conserved DNMT1-dependent methylation regions in human cells are vulnerable to neurotoxicant rotenone exposure
title_fullStr The conserved DNMT1-dependent methylation regions in human cells are vulnerable to neurotoxicant rotenone exposure
title_full_unstemmed The conserved DNMT1-dependent methylation regions in human cells are vulnerable to neurotoxicant rotenone exposure
title_short The conserved DNMT1-dependent methylation regions in human cells are vulnerable to neurotoxicant rotenone exposure
title_sort conserved dnmt1-dependent methylation regions in human cells are vulnerable to neurotoxicant rotenone exposure
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7076959/
https://www.ncbi.nlm.nih.gov/pubmed/32178731
http://dx.doi.org/10.1186/s13072-020-00338-8
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