Low biological fluctuation of mitochondrial CpG and non-CpG methylation at the single-molecule level

Abstract Mammalian cytosine DNA methylation (5mC) is associated with the integrity of the genome and the transcriptional status of nuclear DNA. Due to technical limitations, it has been less clear if mitochondrial DNA (mtDNA) is methylated and whether 5mC has a regulatory role in this context. Here,...

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Autores principales:	Chloe Goldsmith, Jesús Rafael Rodríguez-Aguilera, Ines El-Rifai, Adrien Jarretier-Yuste, Valérie Hervieu, Olivier Raineteau, Pierre Saintigny, Victoria Chagoya de Sánchez, Robert Dante, Gabriel Ichim, Hector Hernandez-Vargas
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/4221444650b74227b0be0661a1952aaf
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spelling	oai:doaj.org-article:4221444650b74227b0be0661a1952aaf2021-12-02T14:26:25ZLow biological fluctuation of mitochondrial CpG and non-CpG methylation at the single-molecule level10.1038/s41598-021-87457-82045-2322https://doaj.org/article/4221444650b74227b0be0661a1952aaf2021-04-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-87457-8https://doaj.org/toc/2045-2322Abstract Mammalian cytosine DNA methylation (5mC) is associated with the integrity of the genome and the transcriptional status of nuclear DNA. Due to technical limitations, it has been less clear if mitochondrial DNA (mtDNA) is methylated and whether 5mC has a regulatory role in this context. Here, we used bisulfite-independent single-molecule sequencing of native human and mouse DNA to study mitochondrial 5mC across different biological conditions. We first validated the ability of long-read nanopore sequencing to detect 5mC in CpG (5mCpG) and non-CpG (5mCpH) context in nuclear DNA at expected genomic locations (i.e. promoters, gene bodies, enhancers, and cell type-specific transcription factor binding sites). Next, using high coverage nanopore sequencing we found low levels of mtDNA CpG and CpH methylation (with several exceptions) and little variation across biological processes: differentiation, oxidative stress, and cancer. 5mCpG and 5mCpH were overall higher in tissues compared to cell lines, with small additional variation between cell lines of different origin. Despite general low levels, global and single-base differences were found in cancer tissues compared to their adjacent counterparts, in particular for 5mCpG. In conclusion, nanopore sequencing is a useful tool for the detection of modified DNA bases on mitochondria that avoid the biases introduced by bisulfite and PCR amplification. Enhanced nanopore basecalling models will provide further resolution on the small size effects detected here, as well as rule out the presence of other DNA modifications such as oxidized forms of 5mC.Chloe GoldsmithJesús Rafael Rodríguez-AguileraInes El-RifaiAdrien Jarretier-YusteValérie HervieuOlivier RaineteauPierre SaintignyVictoria Chagoya de SánchezRobert DanteGabriel IchimHector Hernandez-VargasNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-17 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Chloe Goldsmith Jesús Rafael Rodríguez-Aguilera Ines El-Rifai Adrien Jarretier-Yuste Valérie Hervieu Olivier Raineteau Pierre Saintigny Victoria Chagoya de Sánchez Robert Dante Gabriel Ichim Hector Hernandez-Vargas Low biological fluctuation of mitochondrial CpG and non-CpG methylation at the single-molecule level
description	Abstract Mammalian cytosine DNA methylation (5mC) is associated with the integrity of the genome and the transcriptional status of nuclear DNA. Due to technical limitations, it has been less clear if mitochondrial DNA (mtDNA) is methylated and whether 5mC has a regulatory role in this context. Here, we used bisulfite-independent single-molecule sequencing of native human and mouse DNA to study mitochondrial 5mC across different biological conditions. We first validated the ability of long-read nanopore sequencing to detect 5mC in CpG (5mCpG) and non-CpG (5mCpH) context in nuclear DNA at expected genomic locations (i.e. promoters, gene bodies, enhancers, and cell type-specific transcription factor binding sites). Next, using high coverage nanopore sequencing we found low levels of mtDNA CpG and CpH methylation (with several exceptions) and little variation across biological processes: differentiation, oxidative stress, and cancer. 5mCpG and 5mCpH were overall higher in tissues compared to cell lines, with small additional variation between cell lines of different origin. Despite general low levels, global and single-base differences were found in cancer tissues compared to their adjacent counterparts, in particular for 5mCpG. In conclusion, nanopore sequencing is a useful tool for the detection of modified DNA bases on mitochondria that avoid the biases introduced by bisulfite and PCR amplification. Enhanced nanopore basecalling models will provide further resolution on the small size effects detected here, as well as rule out the presence of other DNA modifications such as oxidized forms of 5mC.
format	article
author	Chloe Goldsmith Jesús Rafael Rodríguez-Aguilera Ines El-Rifai Adrien Jarretier-Yuste Valérie Hervieu Olivier Raineteau Pierre Saintigny Victoria Chagoya de Sánchez Robert Dante Gabriel Ichim Hector Hernandez-Vargas
author_facet	Chloe Goldsmith Jesús Rafael Rodríguez-Aguilera Ines El-Rifai Adrien Jarretier-Yuste Valérie Hervieu Olivier Raineteau Pierre Saintigny Victoria Chagoya de Sánchez Robert Dante Gabriel Ichim Hector Hernandez-Vargas
author_sort	Chloe Goldsmith
title	Low biological fluctuation of mitochondrial CpG and non-CpG methylation at the single-molecule level
title_short	Low biological fluctuation of mitochondrial CpG and non-CpG methylation at the single-molecule level
title_full	Low biological fluctuation of mitochondrial CpG and non-CpG methylation at the single-molecule level
title_fullStr	Low biological fluctuation of mitochondrial CpG and non-CpG methylation at the single-molecule level
title_full_unstemmed	Low biological fluctuation of mitochondrial CpG and non-CpG methylation at the single-molecule level
title_sort	low biological fluctuation of mitochondrial cpg and non-cpg methylation at the single-molecule level
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/4221444650b74227b0be0661a1952aaf
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Low biological fluctuation of mitochondrial CpG and non-CpG methylation at the single-molecule level

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