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

Title: Transcriptome-wide co-expression analysis identifies LRRC2 as a novel mediator of mitochondrial and cardiac function
Authors: McDermott-Roe, C
Leleu, M
Rowe, GC
Palygin, O
Bukowy, JD
Kuo, J
Rech, M
Hermans-Beijnsberger, S
Schaefer, S
Adami, E
Creemers, EE
Heinig, M
Schroen, B
Arany, Z
Petretto, E
Geurts, AM
Item Type: Journal Article
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 genomewide 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-1α. We report that Lrrc2 transcript abundance correlates with that of β-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-1α 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.
Issue Date: 3-Feb-2017
Date of Acceptance: 5-Jan-2017
URI: http://hdl.handle.net/10044/1/57155
DOI: https://dx.doi.org/10.1371/journal.pone.0170458
ISSN: 1932-6203
Publisher: Public Library of Science (PLoS)
Journal / Book Title: PLoS ONE
Volume: 12
Issue: 2
Copyright Statement: © 2017 McDermott-Roe et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Keywords: Science & Technology
Multidisciplinary Sciences
Science & Technology - Other Topics
HEART-FAILURE
PGC-1 COACTIVATORS
GENE-EXPRESSION
HUMAN-DISEASE
PROTEIN
DYSFUNCTION
BIOGENESIS
NETWORK
MUSCLE
CELLS
Animals
Heart Failure
Heat-Shock Proteins
Humans
Leucine-Rich Repeat Serine-Threonine Protein Kinase-2
Mitochondria
Mitochondrial Proteins
Myocytes, Cardiac
Rats
Transcription Factors
Transcriptome
MD Multidisciplinary
General Science & Technology
Publication Status: Published
Article Number: e0170458
Appears in Collections:Clinical Sciences
Molecular Sciences
Faculty of Medicine



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