Modulation of Clock Gene Expression by the Transcriptional Coregulator                 Receptor Interacting Protein 140 (RIP140)

Poliandri, Ariel; Gamsby, Joshua J.; Christian, Mark; Spinella, Michael J.; Loros, Jennifer J.; Dunlap, Jay C.; Parker, Malcolm G.

doi:10.1177/0748730411401579

Cited by 17 publications

(18 citation statements)

References 57 publications

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“…NRIP1 represents a molecular bridge between circadian rhythms and metabolism. It is part of a feedback mechanism regulating the circadian clock: it is under circadian regulation and it can alter basal levels of other clock genes, also by acting as a coactivator for the nuclear receptor RORα, known to be a stimulator of clock genes' transcription (Poliandri et al, 2011 ). RORA has been identified as dysregulated in many tissues from ASD patients (Cook et al, 2015 ).…”

Section: Discussionmentioning

confidence: 99%

Expression and Regulatory Network Analysis of miR-140-3p, a New Potential Serum Biomarker for Autism Spectrum Disorder

Cirnigliaro

Barbagallo

Gulisano

et al. 2017

Front. Mol. Neurosci.

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Given its prevalence and social impact, Autism Spectrum Disorder (ASD) is drawing much interest. Molecular basis of ASD is heterogeneous and only partially known. Many factors, including disorders comorbid with ASD, like TS (Tourette Syndrome), complicate ASD behavior-based diagnosis and make it vulnerable to bias. To further investigate ASD etiology and to identify potential biomarkers to support its precise diagnosis, we used TaqMan Low Density Array technology to profile serum miRNAs from ASD, TS, and TS+ASD patients, and unaffected controls (NCs). Through validation assays in 30 ASD, 24 TS, and 25 TS+ASD patients and 25 NCs, we demonstrated that miR-140-3p is upregulated in ASD vs.: NC, TS, and TS+ASD (Tukey's test, p-values = 0.03, = 0.01, < 0.0001, respectively). ΔCt values for miR-140-3p and YGTSS (Yale Global Tic Severity Scale) scores are positively correlated (Spearman r = 0.33; Benjamini-Hochberg p = 0.008) and show a linear relationship (p = 0.002). Network functional analysis showed that nodes controlled by miR-140-3p, especially CD38 and NRIP1 which are its validated targets, are involved in processes convergingly dysregulated in ASD, such as synaptic plasticity, immune response, and chromatin binding. Biomarker analysis proved that serum miR-140-3p can discriminate among: (1) ASD and NC (Area under the ROC curve, AUC: 0.70; sensitivity: 63.33%; specificity: 68%); (2) ASD and TS (AUC: 0.72; sensitivity: 66.66%; specificity: 70.83%); (3) ASD and TS+ASD (AUC: 0.78; sensitivity: 73.33%; specificity: 76%). Characterization of miR-140-3p network would contribute to further clarify ASD etiology. Serum miR-140-3p could represent a potential non-invasive biomarker for ASD, easy to test through liquid biopsy.

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Section: Discussionmentioning

confidence: 99%

Expression and Regulatory Network Analysis of miR-140-3p, a New Potential Serum Biomarker for Autism Spectrum Disorder

Cirnigliaro

Barbagallo

Gulisano

et al. 2017

Front. Mol. Neurosci.

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“…Other coregulators have been described to play a role in circadian rhythm as well, including NCoR with HDAC3, PGC1-α, RIP140, JARID1a, MAP1a, TRAP150, and several others that influence the activities of both NRs and BMAL1:CLOCK (Curtis et al, 2004; DiTacchio et al, 2011; Feng et al, 2011; Lande-Diner et al, 2013; Li et al, 2013; Liu et al, 2007; Poliandri et al, 2011). We believe that the ability of SRC-2 to positively regulate circadian gene expression is largely achieved by coactivation of BMAL1:CLOCK and by SRC-2 targeting its own promoter, possibly to strengthen gene expression in a feed-forward loop.…”

Section: Discussionmentioning

confidence: 99%

SRC-2 Is an Essential Coactivator for Orchestrating Metabolism and Circadian Rhythm

et al. 2014

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SUMMARY Synchrony of the mammalian circadian clock is achieved by complex transcriptional and translational feedback loops centered on the BMAL1: CLOCK heterodimer. Modulation of circadian feedback loops is essential for maintaining rhythmicity, yet the role of transcriptional coactivators in driving BMAL1:CLOCK transcriptional networks is largely unexplored. Here, we show diurnal hepatic steroid receptor coactivator 2 (SRC-2) recruitment to the genome that extensively overlaps with the BMAL1 cistrome during the light phase, targeting genes that enrich for circadian and metabolic processes. Notably, SRC-2 ablation impairs wheel-running behavior, alters circadian gene expression in several peripheral tissues, alters the rhythmicity of the hepatic metabolome, and deregulates the synchronization of cell-autonomous metabolites. We identify SRC-2 as a potent coregulator of BMAL1:CLOCK and find that SRC-2 targets itself with BMAL1:CLOCK in a feedforward loop. Collectively, our data suggest that SRC-2 is a transcriptional coactivator of the BMAL1:CLOCK oscillators and establish SRC-2 as a critical positive regulator of the mammalian circa-dian clock.

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“…In our screen for proteins containing the PXDLS motif among proteins that play a role in circadian rhythmicity, we identified in addition to REV-ERBα, the NRIP1 and CBP (Figure 7A and B ). NRIP1 regulates Bmal1 expression ( 33 ), while CBP binds to BMAL1 and is implicated in BMAL1/CLOCK transcriptional co-activation ( 34 ). The PXDLS motif is evolutionary conserved in both these proteins (Figure 7A and B ).…”

Section: Resultsmentioning

confidence: 99%

The PXDLS linear motif regulates circadian rhythmicity through protein–protein interactions

Shalev

Aviram

Adamovich

et al. 2014

Nucleic Acids Research

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The circadian core clock circuitry relies on interlocked transcription-translation feedback loops that largely count on multiple protein interactions. The molecular mechanisms implicated in the assembly of these protein complexes are relatively unknown. Our bioinformatics analysis of short linear motifs, implicated in protein interactions, reveals an enrichment of the Pro-X-Asp-Leu-Ser (PXDLS) motif within circadian transcripts. We show that the PXDLS motif can bind to BMAL1/CLOCK and disrupt circadian oscillations in a cell-autonomous manner. Remarkably, the motif is evolutionary conserved in the core clock protein REV-ERBα, and additional proteins implicated in the clock's function (NRIP1, CBP). In this conjuncture, we uncover a novel cross talk between the two principal core clock feedback loops and show that BMAL/CLOCK and REV-ERBα interact and that the PXDLS motif of REV-ERBα participates in their binding. Furthermore, we demonstrate that the PXDLS motifs of NRIP1 and CBP are involved in circadian rhythmicity. Our findings suggest that the PXDLS motif plays an important role in circadian rhythmicity through regulation of protein interactions within the clock circuitry and that short linear motifs can be employed to modulate circadian oscillations.

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Modulation of Clock Gene Expression by the Transcriptional Coregulator Receptor Interacting Protein 140 (RIP140)

Cited by 17 publications

References 57 publications

Expression and Regulatory Network Analysis of miR-140-3p, a New Potential Serum Biomarker for Autism Spectrum Disorder

Expression and Regulatory Network Analysis of miR-140-3p, a New Potential Serum Biomarker for Autism Spectrum Disorder

SRC-2 Is an Essential Coactivator for Orchestrating Metabolism and Circadian Rhythm

The PXDLS linear motif regulates circadian rhythmicity through protein–protein interactions

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