We found that a H3K4 specific histone methyltransferase MLL1, a mammalian homologue of Drosophila trithorax, is essential for circadian transcription. MLL1 is in a complex with CLOCK:BMAL1 and contributes to their rhythmic recruitment to circadian promoters and cyclic H3K4 tri-metylation. To analyze the function of MLL1 on circadian gene regulation, we performed comparative microarray analysis of global gene expression levels in WT and MLL1-deficient MEF, at two different circadian time points (CT18 and CT30). This analysis identified several genes whose expression levels were remarkably changed between CT18 and CT30 in WT and MLL1-KO MEF. Typical clock-regulated genes such as Per2, Per3, Bmal1, or Dbp were found to be changing in WT but not in MLL1-KO MEFs.
The histone methyltransferase MLL1 permits the oscillation of circadian gene expression.
Specimen part, Time
View SamplesThe liver circadian clock is reprogrammed by nutritional challenge through the rewiring of specific transcriptional pathways. As the gut microbiota is tightly connected to host metabolism, whose coordination is governed by the circadian clock, we explored whether gut microbes influence circadian homeostasis and how they distally control the peripheral clock in the liver. Using fecal transplant procedures we reveal that, in response to high fat diet, the gut microbiota drives PPAR-mediated activation of newly oscillatory transcriptional programs in the liver. Moreover, antibiotics treatment prevents PPAR-driven transcription in the liver, underscoring the essential role of gut microbes in clock reprogramming and hepatic circadian homeostasis. Thus, a specific molecular signature characterizes the influence of the gut microbiome in the liver, leading to the transcriptional rewiring of hepatic metabolism.
Gut microbiota directs PPARγ-driven reprogramming of the liver circadian clock by nutritional challenge.
Specimen part
View SamplesThis SuperSeries is composed of the SubSeries listed below.
Cycles in spatial and temporal chromosomal organization driven by the circadian clock.
Specimen part, Disease, Time
View SamplesExpression profiles in WT MEF at different circadian time point after dexamethasone synchronyzation.
Cycles in spatial and temporal chromosomal organization driven by the circadian clock.
Specimen part, Time
View SamplesThe circadian clock orchestrates rhythms in physiology and behavior, allowing the organism to adapt to daily environmental changes. Recently, efforts have been made to unravel the connection between the circadian clock and metabolism and to understand how the peripheral clock in different organs coordinates circadian responses to maintain metabolic homeostasis. It is becoming clear that diet can influence diurnal rhythms, however, the molecular mechanisms responsible for alterations in daily oscillations and how tissue-specific clocks interpret a nutritional challenge are not well understood. Here, we reveal tissue-specific circadian plasticity in response to a ketogenic diet (KD) in both the liver and intestine and a remarkable deviation within these two tissues following subsequent carbohydrate supplementation. KD caused a dramatic change in the circadian transcriptome in both liver and intestine in a tissue-specific fashion. In particular, both the amplitude of clock genes as well as specific BMAL1 recruitment was profoundly altered by KD while the intestinal clock was devoid of such plasticity. While PPARG nuclear accumulation was circadian in both tissues, it showed substantial phase specificity as did downstream targets. Finally, the gut and liver clocks had distinct responses to carbohydrate supplementation to KD composition, suggesting a higher plasticity in the ileum whose gene expression was almost restored to control baseline. For the first time our results demonstrate how nutrients modulate clock function in a tissue-specific manner, suggesting that a food stress arouses unique circadian molecular signatures in distinct peripheral tissues.
Distinct Circadian Signatures in Liver and Gut Clocks Revealed by Ketogenic Diet.
Specimen part
View SamplesGene expression was performed in WT and tumor-bearing (TB) mice to determine the effects of a lung tumor on circadian clock of the liver.
Lung Adenocarcinoma Distally Rewires Hepatic Circadian Homeostasis.
Specimen part, Disease
View SamplesCREM (cAMP responsive element modulator) together with CREB and ATF-1 belong to the CREB family of transcriptional factors, that respond to cyclic AMP signaling and bind to cAMP responsive element (CRE) sites in promoters of selected genes. CREM can produce isoforms that have either activating or repressing functions, depending on the transcription of specific exons. In testis, it is involved in the regulation of spermatogenesis.
Novel insights into the downstream pathways and targets controlled by transcription factors CREM in the testis.
Specimen part, Time
View SamplesCircadian and metabolic processes are codependent. This experiment was designed to understand how a high fat diet affects circadian gene expression in the liver. Circadian gene expression in the liver is necessary for energy balance.
Reprogramming of the circadian clock by nutritional challenge.
Specimen part
View SamplesWe found that the circadian protein PER2 interacts with the nuclear receptor PPARgamma to repress its activity. PPARgamma is a master regulator of adipogenesis and lipid metabolism and is very abundant in adipose tissue. We used microarrays to detail the global program of gene expression in adipose tissue lacking the per2 gene. This analysis identified several PPARgamma target genes up-regulated in adipose tissue from per2-/- mice.
PER2 controls lipid metabolism by direct regulation of PPARγ.
Sex, Age, Specimen part
View SamplesThe circadian gene expression in peripheral tissue displays rhythmicity which is driven by the circadian clock and feeding-fasting cycle in mammals. In this study, circadian transcriptome was performed to investigate how fasting influences circadian gene regulation. Overall design: 8-week-old, male C57BL/6 mice were subjected to 24-hr fasting (FAST) or to ad libitum normal chow feeding (FED) under 12hr light/ 12hr dark schedule. Liver and gastrocnemius muscle were harvested every 4 hours over the circadian cycle at ZT0, 4, 8, 12, 16, 20 (n=3 per time point per group). Total RNA was extracted from liver and gastrocnemius muscle, and used for RNA-seq.
Fasting Imparts a Switch to Alternative Daily Pathways in Liver and Muscle.
Age, Cell line, Subject
View Samples