The Genomic Context and Corecruitment of SP1 Affect ERRα Coactivation by PGC-1α in Muscle Cells

Salatino, Silvia; Kupr, Barbara; Barešić, Mario; Nimwegen, Erik van; Handschin, Christoph

doi:10.1210/me.2016-1036

Cited by 23 publications

(25 citation statements)

References 43 publications

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“…Within the most prominent peak that is located ~7 kilo base (kb) upstream of the BNP TSS, two binding motifs for estrogen-related receptor α (ERRα, ESRRA motif) and one binding site for AP-1 were predicted. Analyses of ERRα ChIP-Seq data13 revealed an overlap of a PGC-1α and an ERRα peak at this genomic location, strongly suggesting co-recruitment of these two proteins. Potent inhibition of ERRα with shRNA and the inverse agonist XCT79014 resulted in a marked reduction of PGC-1α-mediated BNP expression establishing a functional relationship between PGC-1α and ERRα in the control of BNP transcription (Fig.…”

Section: Resultsmentioning

confidence: 95%

Paracrine cross-talk between skeletal muscle and macrophages in exercise by PGC-1α-controlled BNP

Furrer

Eisele

Schmidt

et al. 2017

Sci Rep

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Activation of resident and infiltrating immune cells is a central event in training adaptation and other contexts of skeletal muscle repair and regeneration. A precise orchestration of inflammatory events in muscle fibers and immune cells is required after recurrent contraction-relaxation cycles. However, the mechanistic aspects of this important regulation remain largely unknown. We now demonstrate that besides a dominant role in controlling cellular metabolism, the peroxisome proliferator-activated receptor γ co-activator 1α (PGC-1α) also has a profound effect on cytokine expression in muscle tissue. Muscle PGC-1α expression results in activation of tissue-resident macrophages, at least in part mediated by PGC-1α-dependent B-type natriuretic peptide (BNP) production and secretion. Positive effects of exercise in metabolic diseases and other pathologies associated with chronic inflammation could accordingly involve the PGC-1α-BNP axis and thereby provide novel targets for therapeutic approaches.

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Section: Resultsmentioning

confidence: 95%

Paracrine cross-talk between skeletal muscle and macrophages in exercise by PGC-1α-controlled BNP

Furrer

Eisele

Schmidt

et al. 2017

Sci Rep

Self Cite

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“…PPARA and -G are well-described partners of PPARGC1A [ 34 ]. Recently SP1 and AP-1 have been shown to play a role in the PPARGC1A-controlled gene programme [ 1 , 31 ]. Moreover, a role of SP1, as regulator of cytochrome c expression under conditions of increased contractile activity, has been confirmed previously in murine skeletal muscle cells [ 4 ].…”

Section: Discussionmentioning

confidence: 99%

Intensity-dependent gene expression after aerobic exercise in endurance-trained skeletal muscle

Popov

Makhnovskii

Kurochkina

et al. 2018

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We investigated acute exercise-induced gene expression in skeletal muscle adapted to aerobic training. Vastus lateralis muscle samples were taken in ten endurance-trained males prior to, and just after, 4 h, and 8 h after acute cycling sessions with different intensities, 70% and 50% V˙O2max. High-throughput RNA sequencing was applied in samples from two subjects to evaluate differentially expressed genes after intensive exercise (70% V˙O2max), and then the changes in expression for selected genes were validated by quantitative PCR (qPCR). To define exercise-induced genes, we compared gene expression after acute exercise with different intensities, 70% and 50% V˙O2max, by qPCR. The transcriptome is dynamically changed during the first hours of recovery after intensive exercise (70% V˙O2max). A computational approach revealed that the changes might be related to up- and down-regulation of the activity of transcription activators and repressors, respectively. The exercise increased expression of many genes encoding protein kinases, while genes encoding transcriptional regulators were both up- and down-regulated. Evaluation of the gene expression after exercise with different intensities revealed that some genes changed expression in an intensity-dependent manner, but others did not: the majority of genes encoding protein kinases, oxidative phosphorylation and activator protein (AP)-1-related genes significantly correlated with markers of exercise stress (power, blood lactate during exercise and post-exercise blood cortisol), while transcriptional repressors and circadian-related genes did not. Some of the changes in gene expression after exercise seemingly may be modulated by circadian rhythm.

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“…Correlation scores were calculated using the Spearman correlation coefficient for the Curie cohort and the Pearson correlation coefficient for GSE14020 and GSE12276-GSE2034-GSE2603. P-values < 0.05 were considered statistically significant regulators that had been detected in invasive ductal BCa and as an ERRα transcription control factor-coregulator, respectively [46,47] (Expression-Atlas-EMBL-EBI). Moreover, the RANK/RANKL axis is a critical regulator of BRCA1-mutation-driven BCa and anti-RANKL therapy is now proposed as a preventive strategy for women carrying BRCA1 mutations [37,48].…”

Section: Discussionmentioning

confidence: 99%

ERRα promotes breast cancer cell dissemination to bone by increasing RANK expression in primary breast tumors

et al. 2018

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Bone is the most common metastatic site for breast cancer. Estrogen-related-receptor alpha (ERRα) has been implicated in cancer cell invasiveness. Here, we established that ERRα promotes spontaneous metastatic dissemination of breast cancer cells from primary mammary tumors to the skeleton. We carried out cohort studies, pharmacological inhibition, gain-offunction analyses in vivo and cellular and molecular studies in vitro to identify new biomarkers in breast cancer metastases. Meta-analysis of human primary breast tumors revealed that high ERRα expression levels were associated with bone but not lung metastases. ERRα expression was also detected in circulating tumor cells from metastatic breast cancer patients. ERRα overexpression in murine 4T1 breast cancer cells promoted spontaneous bone micro-metastases formation when tumor cells were inoculated orthotopically, whereas lung metastases occurred irrespective of ERRα expression level. In vivo, Rank was identified as a target for ERRα. That was confirmed in vitro in Rankl stimulated tumor cell invasion, in mTOR/pS6K phosphorylation, by transactivation assay, ChIP and bioinformatics analyses. Moreover, pharmacological inhibition of ERRα reduced primary tumor growth, bone micro-metastases formation and Rank expression in vitro and in vivo. Transcriptomic studies and meta-analysis confirmed a positive association between metastases and ERRα/RANK in breast cancer patients and also revealed a positive correlation between ERRα and BRCA1 mut carriers. Taken together, our results reveal a novel ERRα/RANK axis by which ERRα in primary breast cancer promotes early dissemination of cancer cells to bone. These findings suggest that ERRα may be a useful therapeutic target to prevent bone metastases.

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The Genomic Context and Corecruitment of SP1 Affect ERRα Coactivation by PGC-1α in Muscle Cells

Cited by 23 publications

References 43 publications

Paracrine cross-talk between skeletal muscle and macrophages in exercise by PGC-1α-controlled BNP

Paracrine cross-talk between skeletal muscle and macrophages in exercise by PGC-1α-controlled BNP

Intensity-dependent gene expression after aerobic exercise in endurance-trained skeletal muscle

ERRα promotes breast cancer cell dissemination to bone by increasing RANK expression in primary breast tumors

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