Project description:We address the function of HNF6 in the mouse liver metabolism and Rev-erba cistrome We performed Rev-erba ChIP-seq in mouse livers at 5pm of the day and compared between WT and HNF6-depleted livers.
Project description:We address the function of HNF6 in the mouse liver metabolism and Rev-erba cistrome We performed microarray in mouse livers at 5pm of the day and compared between WT and HNF6-depleted livers.
Project description:The circadian clock regulates behavioural and physiological processes in a 24-h cycle. The nuclear receptors REV-ERBa and REV-ERBb are involved in the cell-autonomous circadian transcriptional/translational feedback loops as transcriptional repressors. A number of studies have also demonstrated a pivotal role of REV-ERBs in regulation of metabolic, neuronal, and inflammatory functions including bile acid metabolism, lipid metabolism, and production of inflammatory cytokines. Given the multifunctional role of REV-ERBs, it is important to elucidate the mechanism through which REV-ERBs exert their functions. To this end, we established a Rev-erba/Rev-erbb double-knockout mouse embryonic stem (ES) cell model and analyzed the circadian clock and clock-controlled output gene expressions. A comprehensive mRNA-seq analysis revealed that the complete knockout of both Rev-erba and Rev-erbb does not abrogate expression rhythms of E-box-regulated core clock genes but drastically changes a diverse set of other rhythmically-expressed output genes. Of note, REV-ERBa/b deficiency does not compromise circadian expression rhythms of PER2, while REV-ERB target genes, Bmal1 and Npas2, are significantly upregulated. This study emphasizes REV-ERBs function to form an essential link between the circadian clock and a wide variety of cellular physiological functions.
Project description:The circadian nature of mood and its dysfunction in affective disorders is well recognized, but the underlying molecular mechanisms are still unclear. We showed that the circadian nuclear receptor REV-ERBa, which is associated with bipolar disorder, impacts midbrain dopamine production and mood-related behavior in mice. Genetic deletion of the Rev-erba gene or pharmacological inhibition of REV-ERBa activity in the ventral midbrain induced mania-like behavior in association with a central hyperdopaminergic state. We used microarrays to identify differentially expressed genes in the ventral midbrains of wild-type (WT) and Rev-erba knock-out (RKO) mice.
Project description:Heart failure remains a major unmet clinical need and current therapies targeting neurohomonal and hemodynamic regulation have limited efficacy. We report that pharmacological activation of the transcriptional repressor REV-ERBa prevents expression of a pathological gene program and cardiomyocyte hypertrophy. In vivo, REV-ERBa agonism prevents development and halts progression of heart failure in mouse models. Thus, modulation of gene networks by targeting REV-ERBa represents a novel approach to heart failure therapy.
Project description:Circadian gene transcription is fundamental to metabolic physiology. Here we report that the nuclear receptor REV-ERBa, a repressive component of the molecular clock, forms circadian condensates in the nuclei of mouse liver. These condensates are dictated by an intrinsically disordered region (IDR) located in the protein’s hinge region which specifically concentrates nuclear receptor corepressor 1 (NCOR1) at the genome. IDR deletion diminishes the recruitment of NCOR1 and disrupts rhythmic gene transcription in vivo. REV-ERBa condensates are located at high-order transcriptional repressive hubs in the liver genome that are highly correlated with circadian gene repression. Deletion of the IDR disrupts transcriptional repressive hubs and diminishes silencing of target genes by REV-ERBa. This work demonstrates physiological circadian protein condensates containing REV-ERBa whose IDR is required for hub formation and the control of rhythmic gene expression.
