Transcriptome-wide co-expression analysis identifies LRRC2 as a novel mediator of mitochondrial and cardiac function.
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 meta-analysis 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-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.
Cardiovascular Center, Medical College of Wisconsin, Milwaukee, WI, United States of America.
Chris
http://orcid.org/0000-0002-2265-8140
C
McDermott-Roe
School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland.
Marion
M
Leleu
Division of Cardiovascular Disease, University of Alabama at Birmingham, Birmingham, AL, United States of America.
Glenn C
GC
Rowe
Cardiovascular Center, Medical College of Wisconsin, Milwaukee, WI, United States of America.
Oleg
O
Palygin
Cardiovascular Center, Medical College of Wisconsin, Milwaukee, WI, United States of America.
John D
JD
Bukowy
Cardiovascular Center, Medical College of Wisconsin, Milwaukee, WI, United States of America.
Judy
J
Kuo
Center for Heart Failure Research, Department of Cardiology, CARIM School for Cardiovascular Diseases, Maastricht University, Maastricht, The Netherlands.
Monika
M
Rech
Center for Heart Failure Research, Department of Cardiology, CARIM School for Cardiovascular Diseases, Maastricht University, Maastricht, The Netherlands.
Steffie
S
Hermans-Beijnsberger
National Heart Research Institute Singapore, National Heart Centre Singapore, Singapore, Singapore.
Sebastian
S
Schaefer
Cardiovascular and Metabolic Sciences, Max Delbrück Center for Molecular Medicine, Berlin, Germany.
Eleonora
E
Adami
Experimental Cardiology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
Esther E
EE
Creemers
Institute of Computational Biology, Helmholtz Zentrum München, Neuherberg, Germany.
Matthias
M
Heinig
Center for Heart Failure Research, Department of Cardiology, CARIM School for Cardiovascular Diseases, Maastricht University, Maastricht, The Netherlands.
Blanche
B
Schroen
Cardiovascular Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
Zoltan
Z
Arany
MRC Clinical Sciences Centre, Imperial College London, London, UK, Duke-NUS Graduate Medical School, Singapore, Singapore.
Enrico
E
Petretto
Cardiovascular Center, Medical College of Wisconsin, Milwaukee, WI, United States of America.
Aron M
AM
Geurts
D000818:Animals; D006333:Heart Failure / Q000235:genetics / Q000378:metabolism; D006360:Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 / Q000235:genetics / Q000378:metabolism; D008928:Mitochondria / Q000378:metabolism*; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000378:metabolism*; D051381:Rats; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D059467:Transcriptome / Q000235:genetics*
D006360:Heat-Shock Proteins; D024101:Mitochondrial Proteins; D014157:Transcription Factors; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2