Abstract
The PGC-1 (Peroxisome proliferator-activated receptor Gamma Coactivator-1) family of coactivators (PGC-1α, PGC-1β, and PRC) plays a central role in the transcriptional control of mitochondrial biogenesis and oxidative phosphorylation (OXPHOS) processes. These coactivators integrate mitochondrial energy production into cell metabolism using complementary pathways. The XTC.UC1 cell line is a mitochondria-rich model of thyroid tumors whose biogenesis is almost exclusively dependent on PRC. Here we aim to propose an integrative view of the cellular pathways regulated by PRC through integration of cDNA and miRNA microarray data and chromatin immunoprecipitation results obtained from XTC.UC1 cells invalidated for PRC. This study showes that PRC induces a complex network of cellular functions interacting with at least one to five of the studied transcription factors (Estrogen Related Receptor alpha, ERR1; Nuclear-Respiratory Factors, NRF1 and NRF2; cAMP Response Element Binding, CREB; and Ying Yang, YY1). Our data confirm that ERR1 is a key partner of PRC in the regulation of mitochondrial functions and suggest a potential role of this complex in RNA processing. PRC is also involved in transcriptional regulatory complexes targeting 12 miRNAs, five of which are involved in the control of the OXPHOS process. Our findings demonstrate that the PRC coactivator can act in complex with several transcription factors and regulate miRNA expression to control the fine regulation of main metabolic functions in the cell. Therefore, in PGC-1α/β-associated pathologies, PRC, as a metabolic sensor, may ensure mitochondrial homeostasis.
Highlights
Metabolic adaptation involves regulation of energy homeostasis at the transcriptional and postranscriptional levels using diverse transcription factors, coregulators and feed-back control loops [1]
Using both transcriptomic and quantitative PCR analyses we have previously shown www.oncotarget.com that the XTC.UC1 cell line expresses very low levels of PGC-1α and -1β factors compared to the PRC expression level [7, 16, 17]
This cellular model is relevant to study transcriptional and post-transcriptional factors that are able to conduct PRC-dependent mitochondrial biogenesis and function because of its high dependence on this ubiquitous and serum induced member of the PGC1 family of coactivators [17]
Summary
Metabolic adaptation involves regulation of energy homeostasis at the transcriptional and postranscriptional levels using diverse transcription factors, coregulators and feed-back control loops [1]. The mechanism controlling nucleusmitochondrial crosstalk may need co-expression of many factors considering a long-term adaptive response for www.oncotarget.com mitochondrial biogenesis. Studies on several transcription factors regulating mitochondrial biogenesis and function have shown extensive use of feed-forward and feedback loops to control this biogenesis [2,3,4]. Master transcriptional coregulators like Peroxisome proliferator-activated receptor Gamma Coactivator 1 (PGC-1α) and related family members (PGC-1β and PGC-1-Related Coactivator or PRC) may interact with some of these transcription factors and exhibit a unique capacity to control complex transcriptional networks and remodel the metabolic landscape
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