1. Chromosomes and Gene Expression
  2. Genetics and Genomics

Nuclear genetic regulation of the human mitochondrial transcriptome

  1. Aminah T Ali
  2. Lena Boehme
  3. Guillermo Carbajosa
  4. Vlad C Seitan
  5. Kerrin S Small
  6. Alan Hodgkinson  Is a corresponding author
  1. King's College London, United Kingdom
https://doi.org/10.7554/eLife.41927
Share this article
Cite this article
  1. Aminah T Ali
  2. Lena Boehme
  3. Guillermo Carbajosa
  4. Vlad C Seitan
  5. Kerrin S Small
  6. Alan Hodgkinson
(2019)
Nuclear genetic regulation of the human mitochondrial transcriptome
eLife 8:e41927.
https://doi.org/10.7554/eLife.41927
  2. Download BibTeX
  3. Download .RIS

Abstract

Mitochondria play important roles in cellular processes and disease, yet little is known about how the transcriptional regime of the mitochondrial genome varies across individuals and tissues. By analyzing >11,000 RNA-sequencing libraries across 36 tissue/cell types, we find considerable variation in mitochondrial-encoded gene expression along the mitochondrial transcriptome, across tissues and between individuals, highlighting the importance of cell-type specific and post-transcriptional processes in shaping mitochondrial-encoded RNA levels. Using whole-genome genetic data we identify 64 nuclear loci associated with expression levels of 14 genes encoded in the mitochondrial genome, including missense variants within genes involved in mitochondrial function (TBRG4, MTPAP and LONP1), implicating genetic mechanisms that act in trans across the two genomes. We replicate ~21% of associations with independent tissue-matched datasets and find genetic variants linked to these nuclear loci that are associated with cardio-metabolic phenotypes and Vitiligo, supporting a potential role for variable mitochondrial-encoded gene expression in complex disease.

Data availability

Anonymized processed mitochondrial encoded gene expression matrices are available in supplementary file 2 and from the Gene Expression Omnibus under accession GSE125013

The following data sets were generated
The following previously published data sets were used

Article and author information

Author details

  1. Aminah T Ali

    Department of Medical and Molecular Genetics, King's College London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-1089-9278

  2. Lena Boehme

    Department of Medical and Molecular Genetics, King's College London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-7593-7533

  3. Guillermo Carbajosa

    Department of Medical and Molecular Genetics, King's College London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.

  4. Vlad C Seitan

    Department of Medical and Molecular Genetics, King's College London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.

  5. Kerrin S Small

    Department of Twin Research and Genetic Epidemiology, King's College London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-4566-0005

  6. Alan Hodgkinson

    Department of Medical and Molecular Genetics, King's College London, London, United Kingdom
    For correspondence
    alan.hodgkinson@kcl.ac.uk
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-1636-491X

Funding

Medical Research Council (MR/L016311/1)

  • Alan Hodgkinson

Biotechnology and Biological Sciences Research Council (BB/R006075/1)

  • Guillermo Carbajosa
  • Alan Hodgkinson

People Programme of the European Union's Seventh Framework Programme (FP7/2007-2013)

  • Alan Hodgkinson

Generation trust

  • Aminah T Ali

Medical Research Council (MR/L01999X/1)

  • Kerrin S Small

Medical Research Council (MR/M009343/1)

  • Vlad C Seitan

Guy's and St. Thomas' Charity (MAJ110901)

  • Lena Boehme

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Alexis Battle, John Hopkins School of Medicine, United States

Version history

  1. Received: September 11, 2018
  2. Accepted: February 14, 2019
  3. Accepted Manuscript published: February 18, 2019 (version 1)
  4. Version of Record published: March 15, 2019 (version 2)

Copyright

© 2019, Ali et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

Metrics

  • 11,969
    views
  • 1,193
    downloads
  • 53
    citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  1. Aminah T Ali
  2. Lena Boehme
  3. Guillermo Carbajosa
  4. Vlad C Seitan
  5. Kerrin S Small
  6. Alan Hodgkinson
(2019)
Nuclear genetic regulation of the human mitochondrial transcriptome
eLife 8:e41927.
https://doi.org/10.7554/eLife.41927

Share this article

https://doi.org/10.7554/eLife.41927

Categories and tags

Research organism

Further reading

    1. Chromosomes and Gene Expression
    2. Genetics and Genomics

    Evolutionary adaptation of an HP1-protein chromodomain integrates chromatin and DNA sequence signals

    Lisa Baumgartner, Jonathan J Ipsaro ... Julius Brennecke
    Research Advance

    Members of the diverse heterochromatin protein 1 (HP1) family play crucial roles in heterochromatin formation and maintenance. Despite the similar affinities of their chromodomains for di- and tri-methylated histone H3 lysine 9 (H3K9me2/3), different HP1 proteins exhibit distinct chromatin-binding patterns, likely due to interactions with various specificity factors. Previously, we showed that the chromatin-binding pattern of the HP1 protein Rhino, a crucial factor of the Drosophila PIWI-interacting RNA (piRNA) pathway, is largely defined by a DNA sequence-specific C2H2 zinc finger protein named Kipferl (Baumgartner et al., 2022). Here, we elucidate the molecular basis of the interaction between Rhino and its guidance factor Kipferl. Through phylogenetic analyses, structure prediction, and in vivo genetics, we identify a single amino acid change within Rhino’s chromodomain, G31D, that does not affect H3K9me2/3 binding but disrupts the interaction between Rhino and Kipferl. Flies carrying the rhinoG31D mutation phenocopy kipferl mutant flies, with Rhino redistributing from piRNA clusters to satellite repeats, causing pronounced changes in the ovarian piRNA profile of rhinoG31D flies. Thus, Rhino’s chromodomain functions as a dual-specificity module, facilitating interactions with both a histone mark and a DNA-binding protein.

    1. Biochemistry and Chemical Biology
    2. Chromosomes and Gene Expression

    Human DDX6 regulates translation and decay of inefficiently translated mRNAs

    Ramona Weber, Chung-Te Chang
    Research Article

    Recent findings indicate that the translation elongation rate influences mRNA stability. One of the factors that has been implicated in this link between mRNA decay and translation speed is the yeast DEAD-box helicase Dhh1p. Here, we demonstrated that the human ortholog of Dhh1p, DDX6, triggers the deadenylation-dependent decay of inefficiently translated mRNAs in human cells. DDX6 interacts with the ribosome through the Phe-Asp-Phe (FDF) motif in its RecA2 domain. Furthermore, RecA2-mediated interactions and ATPase activity are both required for DDX6 to destabilize inefficiently translated mRNAs. Using ribosome profiling and RNA sequencing, we identified two classes of endogenous mRNAs that are regulated in a DDX6-dependent manner. The identified targets are either translationally regulated or regulated at the steady-state-level and either exhibit signatures of poor overall translation or of locally reduced ribosome translocation rates. Transferring the identified sequence stretches into a reporter mRNA caused translation- and DDX6-dependent degradation of the reporter mRNA. In summary, these results identify DDX6 as a crucial regulator of mRNA translation and decay triggered by slow ribosome movement and provide insights into the mechanism by which DDX6 destabilizes inefficiently translated mRNAs.

    1. Chromosomes and Gene Expression

    Comparative transcriptomics reveal a novel tardigrade-specific DNA-binding protein induced in response to ionizing radiation

    Marwan Anoud, Emmanuelle Delagoutte ... Jean-Paul Concordet
    Research Article

    Tardigrades are microscopic animals renowned for their ability to withstand extreme conditions, including high doses of ionizing radiation (IR). To better understand their radio-resistance, we first characterized induction and repair of DNA double- and single-strand breaks after exposure to IR in the model species Hypsibius exemplaris. Importantly, we found that the rate of single-strand breaks induced was roughly equivalent to that in human cells, suggesting that DNA repair plays a predominant role in tardigrades’ radio-resistance. To identify novel tardigrade-specific genes involved, we next conducted a comparative transcriptomics analysis across three different species. In all three species, many DNA repair genes were among the most strongly overexpressed genes alongside a novel tardigrade-specific gene, which we named Tardigrade DNA damage Response 1 (TDR1). We found that TDR1 protein interacts with DNA and forms aggregates at high concentration suggesting it may condensate DNA and preserve chromosome organization until DNA repair is accomplished. Remarkably, when expressed in human cells, TDR1 improved resistance to Bleomycin, a radiomimetic drug. Based on these findings, we propose that TDR1 is a novel tardigrade-specific gene conferring resistance to IR. Our study sheds light on mechanisms of DNA repair helping cope with high levels of DNA damage inflicted by IR.