Malignancy and NF-κB signalling strengthen coordination between expression of mitochondrial and nuclear-encoded oxidative phosphorylation genes

Abstract Background Mitochondria are ancient endosymbiotic organelles crucial to eukaryotic growth and metabolism. The mammalian mitochondrial genome encodes for 13 mitochondrial proteins, and the remaining mitochondrial proteins are encoded by the nuclear genome. Little is known about how coordinat...

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Autores principales:	Marcos Francisco Perez, Peter Sarkies
Formato:	article
Lenguaje:	EN
Publicado:	BMC 2021
Materias:	Biology (General) QH301-705.5 Genetics QH426-470
Acceso en línea:	https://doaj.org/article/44a861d5652d4bcf8aeb6cd269743486
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spelling	oai:doaj.org-article:44a861d5652d4bcf8aeb6cd2697434862021-12-05T12:25:37ZMalignancy and NF-κB signalling strengthen coordination between expression of mitochondrial and nuclear-encoded oxidative phosphorylation genes10.1186/s13059-021-02541-61474-760Xhttps://doaj.org/article/44a861d5652d4bcf8aeb6cd2697434862021-12-01T00:00:00Zhttps://doi.org/10.1186/s13059-021-02541-6https://doaj.org/toc/1474-760XAbstract Background Mitochondria are ancient endosymbiotic organelles crucial to eukaryotic growth and metabolism. The mammalian mitochondrial genome encodes for 13 mitochondrial proteins, and the remaining mitochondrial proteins are encoded by the nuclear genome. Little is known about how coordination between the expression of the two sets of genes is achieved. Results Correlation analysis of RNA-seq expression data from large publicly available datasets is a common method to leverage genetic diversity to infer gene co-expression modules. Here we use this method to investigate nuclear-mitochondrial gene expression coordination. We identify a pitfall in correlation analysis that results from the large variation in the proportion of transcripts from the mitochondrial genome in RNA-seq data. Commonly used normalisation techniques based on total read counts, such as FPKM or TPM, produce artefactual negative correlations between mitochondrial- and nuclear-encoded transcripts. This also results in artefactual correlations between pairs of nuclear-encoded genes, with important consequences for inferring co-expression modules beyond mitochondria. We show that these effects can be overcome by normalizing using the median-ratio normalisation (MRN) or trimmed mean of M values (TMM) methods. Using these normalisations, we find only weak and inconsistent correlations between mitochondrial and nuclear-encoded mitochondrial genes in the majority of healthy human tissues from the GTEx database. Conclusions We show that a subset of healthy tissues with high expression of NF-κB show significant coordination, suggesting a role for NF-κB in ensuring balanced expression between mitochondrial and nuclear genes. Contrastingly, most cancer types show robust coordination of nuclear and mitochondrial OXPHOS gene expression, identifying this as a feature of gene regulation in cancer.Marcos Francisco PerezPeter SarkiesBMCarticleBiology (General)QH301-705.5GeneticsQH426-470ENGenome Biology, Vol 22, Iss 1, Pp 1-24 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Biology (General) QH301-705.5 Genetics QH426-470
spellingShingle	Biology (General) QH301-705.5 Genetics QH426-470 Marcos Francisco Perez Peter Sarkies Malignancy and NF-κB signalling strengthen coordination between expression of mitochondrial and nuclear-encoded oxidative phosphorylation genes
description	Abstract Background Mitochondria are ancient endosymbiotic organelles crucial to eukaryotic growth and metabolism. The mammalian mitochondrial genome encodes for 13 mitochondrial proteins, and the remaining mitochondrial proteins are encoded by the nuclear genome. Little is known about how coordination between the expression of the two sets of genes is achieved. Results Correlation analysis of RNA-seq expression data from large publicly available datasets is a common method to leverage genetic diversity to infer gene co-expression modules. Here we use this method to investigate nuclear-mitochondrial gene expression coordination. We identify a pitfall in correlation analysis that results from the large variation in the proportion of transcripts from the mitochondrial genome in RNA-seq data. Commonly used normalisation techniques based on total read counts, such as FPKM or TPM, produce artefactual negative correlations between mitochondrial- and nuclear-encoded transcripts. This also results in artefactual correlations between pairs of nuclear-encoded genes, with important consequences for inferring co-expression modules beyond mitochondria. We show that these effects can be overcome by normalizing using the median-ratio normalisation (MRN) or trimmed mean of M values (TMM) methods. Using these normalisations, we find only weak and inconsistent correlations between mitochondrial and nuclear-encoded mitochondrial genes in the majority of healthy human tissues from the GTEx database. Conclusions We show that a subset of healthy tissues with high expression of NF-κB show significant coordination, suggesting a role for NF-κB in ensuring balanced expression between mitochondrial and nuclear genes. Contrastingly, most cancer types show robust coordination of nuclear and mitochondrial OXPHOS gene expression, identifying this as a feature of gene regulation in cancer.
format	article
author	Marcos Francisco Perez Peter Sarkies
author_facet	Marcos Francisco Perez Peter Sarkies
author_sort	Marcos Francisco Perez
title	Malignancy and NF-κB signalling strengthen coordination between expression of mitochondrial and nuclear-encoded oxidative phosphorylation genes
title_short	Malignancy and NF-κB signalling strengthen coordination between expression of mitochondrial and nuclear-encoded oxidative phosphorylation genes
title_full	Malignancy and NF-κB signalling strengthen coordination between expression of mitochondrial and nuclear-encoded oxidative phosphorylation genes
title_fullStr	Malignancy and NF-κB signalling strengthen coordination between expression of mitochondrial and nuclear-encoded oxidative phosphorylation genes
title_full_unstemmed	Malignancy and NF-κB signalling strengthen coordination between expression of mitochondrial and nuclear-encoded oxidative phosphorylation genes
title_sort	malignancy and nf-κb signalling strengthen coordination between expression of mitochondrial and nuclear-encoded oxidative phosphorylation genes
publisher	BMC
publishDate	2021
url	https://doaj.org/article/44a861d5652d4bcf8aeb6cd269743486
work_keys_str_mv	AT marcosfranciscoperez malignancyandnfkbsignallingstrengthencoordinationbetweenexpressionofmitochondrialandnuclearencodedoxidativephosphorylationgenes AT petersarkies malignancyandnfkbsignallingstrengthencoordinationbetweenexpressionofmitochondrialandnuclearencodedoxidativephosphorylationgenes
_version_	1718371953326161920

Malignancy and NF-κB signalling strengthen coordination between expression of mitochondrial and nuclear-encoded oxidative phosphorylation genes

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