The circadian clock gene Bmal1 facilitates cisplatin-induced renal injury and hepatization
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ABSTRACT:
PROVIDER: PRJNA627591 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR11594396_1.fastq.gz | Fastqsanger.gz | |||
| SRR11594396_2.fastq.gz | Fastqsanger.gz | |||
| SRR11594397_1.fastq.gz | Fastqsanger.gz | |||
| SRR11594397_2.fastq.gz | Fastqsanger.gz |
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Project description:Cisplatin is one of the most potent chemotherapy drugs to treat cancers, but its clinical application remains limited due to severe nephrotoxicity. Several approaches have been developed to minimize such side effects, notably including chronotherapy, a well-known strategy based on the circadian clock. However, the component of the circadian clock machinery that particularly responses to the cisplatin stimulation remains unknown, including its functions in cisplatin-induced renal injury. In our present study, we demonstrated that Bmal1, as a key clock gene, was induced by the cisplatin stimulation in the mouse kidney and cultured human HK-2 renal cells. Gain- and loss-of-function studies indicated that Bmal1 facilitated cisplatin-induced renal injury both in vivo and in vitro, by aggravating the cell apoptotic process. More importantly, RNA-seq analysis revealed that Bmal1 triggered the expression of hallmark genes involved in renal hepatization, a critical event accompanied by the injury. At the molecular level, Bmal1 activated the transcription of hepatization-associated genes through direct recruitment to the E-box motifs of their promoters. Our findings suggest that Bmal1, a pivotal mediator induced renal injury in response to cisplatin treatment, and the therapeutic intervention targeting Bmal1 in the kidney may be a promising strategy to minimize the toxic side-effects of cisplatin in its clinical applications.
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Project description:Circadian rhythmicity in renal function suggests a requirement for circadian adaptations in renal metabolism. We studied circadian changes in renal metabolic pathways using integrated transcriptomic, proteomic and metabolomic analysis performed on control mice and mice deficient in the circadian clock gene Bmal1 in the renal tubule (cKOt mice). Proteins were extracted from whole kidneys of 60 mice. Of these, 30 were conditional knockouts of Arntl (Bmal1) and 30 were of control genotype. They were housed under 12-hours light/12-hours dark cycles and were sacrificed at six different time points: zeitgeber time ZT 0, ZT 4, ZT 8, ZT 12, ZT 16, ZT 20 ( ZT 0 being the time of light on and ZT 12 the time of light off). Five replicates per genotype and time point were analysed.
2023-03-15 | PXD036803 | Pride
Project description:In mammals, circadian clocks are strictly suppressed during early embryonic stages as well as pluripotent stem cells, by the lack of CLOCK/BMAL1 mediated circadian feedback loops. During ontogenesis, the innate circadian clocks emerge gradually at a late developmental stage, then, with which the circadian temporal order is invested in each cell level throughout a body. Meanwhile, in the early developmental stage, a segmented body plan is essential for an intact developmental process and somitogenesis is controlled by another cell-autonomous oscillator, the segmentation clock, in the posterior presomitic mesoderm (PSM). In the present study, focusing upon the interaction between circadian key components and the segmentation clock, we investigated the effect of the CLOCK/BMAL1 on the segmentation clock Hes7 oscillation, revealing that the expression of functional CLOCK/BMAL1 severely interferes with the ultradian rhythm of segmentation clock in induced PSM and gastruloids. RNA sequencing analysis showed that the premature expression of CLOCK/BMAL1 affects the Hes7 transcription and its regulatory pathways. These results suggest that the suppression of CLOCK/BMAL1-mediated transcriptional regulation during the somitogenesis may be inevitable for intact mammalian development.
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Project description:The mammalian circadian clock is a molecular oscillator composed of a feedback loop that involves transcriptional activators CLOCK and BMAL1, and repressors Cryptochrome (CRY) and Period (PER). Here we show that a direct CLOCK-BMAL1 target gene, Gm129, is a novel regulator of the feedback loop. ChIP analysis revealed that the CLOCK:BMAL1:CRY1 complex strongly occupies the promoter region of Gm129. Both mRNA and protein levels of GM129 exhibit high amplitude circadian oscillations in mouse liver, and Gm129 gene encodes a nuclear-localized protein that directly interacts with BMAL1 and represses CLOCK:BMAL1 activity. In vitro and in vivo protein-DNA interaction results demonstrate that, like CRY1, GM129 functions as a repressor by binding to the CLOCK:BMAL1 complex on DNA. Although Gm129-/- or Cry1-/- Gm129-/- mice retain a robust circadian rhythm, the peaks of Nr1d1 and Dbp mRNAs in liver exhibit significant phase delay compared to control. Our results suggest that, in addition to CRYs and PERs, GM129 protein contributes to the transcriptional feedback loop by modulating CLOCK:BMAL1 activity as a transcriptional repressor. Examination of 3 transcriptional regulators in mouse liver
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Project description:Circadian rhythmicity in renal function suggests rhythmic adaptations in renal metabolism. To decipher the role of the circadian clock in renal metabolism, we studied diurnal changes in renal metabolic pathways using integrated transcriptomic, proteomic, and metabolomic analysis performed on control mice and mice with inducible deletion of the circadian clock regulator Bmal1 in the renal tubule (cKOt). With this unique resource, we demonstrated that ~30% RNAs, ~20% proteins and ~20% metabolites are rhythmic in kidneys of control mice. Several key metabolic pathways including NAD+ biosynthesis, fatty acid transport, carnitine shuttle, and b-oxidation displayed impairments in kidneys of cKOt, resulting in a perturbed mitochondrial activity. Carnitine reabsorption from the primary urine was one of the most impacted processes with a ~50% reduction in plasma carnitine levels and a parallel systemic decrease in tissues carnitine content. This suggests that the circadian clock in the renal tubule controls both kidney and systemic physiology.
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Project description:The human osteosarcoma cell line U2OS contains a functional circadian clock but expresses only a few rhythmic genes. We identified by ChIP-seq analysis 3040 binding sites of the circadian transcription factors BMAL1, CLOCK, and CRY1 in the genome of U2OS cells, comparable to the number found in highly rhythmic tissues like liver. ChIP was performed as described previously (Rey et al, 2011; doi:10.1371/journal.pbio.1000595) using confluent desynchronized U2OS cells and BMAL1, CLOCK, and CRY1-antibodies. Immunoprecipitated chromatin (10 ng DNA of 8 independent BMAL1 ChIPs with enrichment levels > 80-fold, 9 ng DNA of a CRY1 ChIP with 10-fold enrichment, and 8 ng DNA of a CLOCK ChIP with 40-fold enrichment) was used for library preparation. Three lanes of the BMAL1 library, and one lane each of the CRY1 and CLOCK library were sequenced on the Illumina Genome Analyzer IIx using Single-Read Cluster Generation Kit and 36 Cycle Sequencing Kit v2 (Lausanne Genomics Technologies Facility).
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Project description:Circadian clocks exist in almost all levels of living organisms and play elementary roles in the persistence of regular physiological and behavioural processes. Canonical transcription/translation feedback loop models portray BMAL1 (ARNTL) as one of the principal drivers of circadian periodicity in mammalian systems. In this integrated multi-omics study, we demonstrate, for the first time, 24 hr circadian oscillations in the expression levels of several transcripts and proteins in dexamethasone-synchronized Bmal1-/- mouse fibroblast cells and liver tissue slices. Intriguingly, daily oscillations were also observed in phosphoproteome profiles in the absence of this core clock gene. Our findings reveal that Bmal1 knockout radically alters the expression and phosphorylation patterns of mice hepatic proteome, which possibly attributes to considerably different sets of rhythmic candidates compared to wild-type. It is, therefore, reasonable to accentuate that circadian rhythms are not obliterated in mammalian systems due to deletion of the core clock genes.
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Project description:In diabetes, the kidney contributes to the development of diabetic hyperglycemia by increasing glucose reabsorption from the primary urine and by upregulating gluconeogenesis in the proximal tubule. However, these two processes are also controlled by the circadian clock, a mechanism that synchronizes a large number of specific renal functions with environmental daily cycles. Here, we investigated the (patho)physiological role of intrinsic renal tubule circadian clocks in the diabetic kidney. We demonstrate that diabetic mice devoid of the circadian transcriptional regulator BMAL1 in the renal tubule exhibit additional enhancement of renal gluconeogenesis, exacerbated hyperglycemia, increased glucosuria, polyuria and renal hypertrophy. Collectively, our results suggest that diabetic hyperglycemia can be worsened by dysfunction or misalignment of intrinsic renal circadian clocks.
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