Transcriptome-wide co-expression analysis identifies LRRC2 as a novel mediator of mitochondrial and cardiac function

Chris McDermott-Roe*, Marion Leleu, Glenn C. Rowe, Oleg Palygin, John D. Bukowy, Judy Kuo, Monika Rech, Steffie Hermans-Beijnsberger, Sebastian Schaefer, Eleonora Adami, Esther E. Creemers, Matthias Heinig, Blanche Schroen, Zoltan Arany, Enrico Petretto, Aron M. Geurts

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

6 Citations (Web of Science)

Abstract

Mitochondrial dysfunction contributes to myriad monogenic and complex pathologies. To understand the underlying mechanisms, it is essential to define the full complement of proteins that modulate mitochondrial function. To identify such proteins, we performed a metaanalysis of publicly available gene expression data. Gene co-expression analysis of a large and heterogeneous compendium of microarray data nominated a sub-population of transcripts that whilst highly correlated with known mitochondrial protein-encoding transcripts (MPETs), are not themselves recognized as generating proteins either localized to the mitochondrion or pertinent to functions therein. To focus the analysis on a medically-important condition with a strong yet incompletely understood mitochondrial component, candidates were cross-referenced with an MPET-enriched module independently generated via genome-wide co-expression network analysis of a human heart failure gene expression dataset. The strongest uncharacterized candidate in the analysis was Leucine Rich Repeat Containing 2 (LRRC2). LRRC2 was found to be localized to the mitochondria in human cells and transcriptionally- regulated by the mitochondrial master regulator Pgc-1 alpha. We report that Lrrc2 transcript abundance correlates with that of beta-MHC, a canonical marker of cardiac hypertrophy in humans and experimentally demonstrated an elevation in Lrrc2 transcript in in vitro and in vivo rodent models of cardiac hypertrophy as well as in patients with dilated cardiomyopathy. RNAi-mediated Lrrc2 knockdown in a rat-derived cardiomyocyte cell line resulted in enhanced expression of canonical hypertrophic biomarkers as well as increased mitochondrial mass in the context of increased Pgc-1 alpha expression. In conclusion, our meta-analysis represents a simple yet powerful springboard for the nomination of putative mitochondrially-pertinent proteins relevant to cardiac function and enabled the identification of LRRC2 as a novel mitochondrially- relevant protein and regulator of the hypertrophic response.

Original languageEnglish
Article number0170458
Number of pages20
JournalPLOS ONE
Volume12
Issue number2
DOIs
Publication statusPublished - 3 Feb 2017

Keywords

  • HEART-FAILURE
  • PGC-1 COACTIVATORS
  • GENE-EXPRESSION
  • HUMAN-DISEASE
  • PROTEIN
  • DYSFUNCTION
  • BIOGENESIS
  • NETWORK
  • MUSCLE
  • CELLS

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