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 ge...
Saved in:
| Main Authors: | , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2017-01-01
|
| Series: | PLoS ONE |
| Online Access: | https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0170458&type=printable |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1849467583295651840 |
|---|---|
| author | 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 |
| author_facet | 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 |
| author_sort | Chris McDermott-Roe |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-32ee4dc91d374bd4874942d7b45e8553 |
| institution | Kabale University |
| issn | 1932-6203 |
| language | English |
| publishDate | 2017-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj-art-32ee4dc91d374bd4874942d7b45e85532025-08-20T03:26:10ZengPublic Library of Science (PLoS)PLoS ONE1932-62032017-01-01122e017045810.1371/journal.pone.0170458Transcriptome-wide co-expression analysis identifies LRRC2 as a novel mediator of mitochondrial and cardiac function.Chris McDermott-RoeMarion LeleuGlenn C RoweOleg PalyginJohn D BukowyJudy KuoMonika RechSteffie Hermans-BeijnsbergerSebastian SchaeferEleonora AdamiEsther E CreemersMatthias HeinigBlanche SchroenZoltan AranyEnrico PetrettoAron M GeurtsMitochondrial 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.https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0170458&type=printable |
| spellingShingle | 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 Transcriptome-wide co-expression analysis identifies LRRC2 as a novel mediator of mitochondrial and cardiac function. PLoS ONE |
| title | Transcriptome-wide co-expression analysis identifies LRRC2 as a novel mediator of mitochondrial and cardiac function. |
| title_full | Transcriptome-wide co-expression analysis identifies LRRC2 as a novel mediator of mitochondrial and cardiac function. |
| title_fullStr | Transcriptome-wide co-expression analysis identifies LRRC2 as a novel mediator of mitochondrial and cardiac function. |
| title_full_unstemmed | Transcriptome-wide co-expression analysis identifies LRRC2 as a novel mediator of mitochondrial and cardiac function. |
| title_short | Transcriptome-wide co-expression analysis identifies LRRC2 as a novel mediator of mitochondrial and cardiac function. |
| title_sort | transcriptome wide co expression analysis identifies lrrc2 as a novel mediator of mitochondrial and cardiac function |
| url | https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0170458&type=printable |
| work_keys_str_mv | AT chrismcdermottroe transcriptomewidecoexpressionanalysisidentifieslrrc2asanovelmediatorofmitochondrialandcardiacfunction AT marionleleu transcriptomewidecoexpressionanalysisidentifieslrrc2asanovelmediatorofmitochondrialandcardiacfunction AT glenncrowe transcriptomewidecoexpressionanalysisidentifieslrrc2asanovelmediatorofmitochondrialandcardiacfunction AT olegpalygin transcriptomewidecoexpressionanalysisidentifieslrrc2asanovelmediatorofmitochondrialandcardiacfunction AT johndbukowy transcriptomewidecoexpressionanalysisidentifieslrrc2asanovelmediatorofmitochondrialandcardiacfunction AT judykuo transcriptomewidecoexpressionanalysisidentifieslrrc2asanovelmediatorofmitochondrialandcardiacfunction AT monikarech transcriptomewidecoexpressionanalysisidentifieslrrc2asanovelmediatorofmitochondrialandcardiacfunction AT steffiehermansbeijnsberger transcriptomewidecoexpressionanalysisidentifieslrrc2asanovelmediatorofmitochondrialandcardiacfunction AT sebastianschaefer transcriptomewidecoexpressionanalysisidentifieslrrc2asanovelmediatorofmitochondrialandcardiacfunction AT eleonoraadami transcriptomewidecoexpressionanalysisidentifieslrrc2asanovelmediatorofmitochondrialandcardiacfunction AT estherecreemers transcriptomewidecoexpressionanalysisidentifieslrrc2asanovelmediatorofmitochondrialandcardiacfunction AT matthiasheinig transcriptomewidecoexpressionanalysisidentifieslrrc2asanovelmediatorofmitochondrialandcardiacfunction AT blancheschroen transcriptomewidecoexpressionanalysisidentifieslrrc2asanovelmediatorofmitochondrialandcardiacfunction AT zoltanarany transcriptomewidecoexpressionanalysisidentifieslrrc2asanovelmediatorofmitochondrialandcardiacfunction AT enricopetretto transcriptomewidecoexpressionanalysisidentifieslrrc2asanovelmediatorofmitochondrialandcardiacfunction AT aronmgeurts transcriptomewidecoexpressionanalysisidentifieslrrc2asanovelmediatorofmitochondrialandcardiacfunction |