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Temporal profiles of gene expression in Cry1/2 KO, Bmal1 KO under night restricted feeding and ad libitum feeding regimen

ABSTRACT: The circadian clock and rhythmic food intake are both important regulators of rhythmic gene expression in the liver. It remains, however, elusive to which extent the circadian clock network and natural feeding rhythms contribute to rhythmic gene expression. To systematically address this question, we developed an algorithm to investigate differential rhythmicity between a varying number of conditions. Mouse knockout models of different parts of the circadian clock network (Bmal1, Cry1/2, and Hlf/Dbp/Tef) exposed to controlled feeding regimens (ad libitum, night restricted feeding) were generated and analyzed for their temporal hepatic transcriptome. A genetical ablation of core loop elements altered feeding patterns that were restored by night restricted feeding. Mainly genes with a high amplitude were driven by the circadian clock but natural feeding patterns equally contributed to rhythmic gene expression with lower amplitude. We observed that Bmal1 and Cry1/2 KOs differed in rhythmic gene expression and identified differences in mean expression levels as a predictor for rhythmic gene expression. In Hlf/Dbp/Tef KO, mRNA levels of Hlf/Dbp/Tef target genes were decreased, albeit rhythmicity was overall preserved potentially due to the activity of the D-Box binding repressor NFIL3. Genes that lost rhythmicity in Hlf/Dbp/Tef KOs were identified to be no direct targets of PARbZip factors and presumably lost rhythmicity due to indirect effects. Collectively, our findings provide unprecedent insights into the diurnal transcriptome in mouse liver and defines the contribution of subloops of the circadian clock network and natural feeding cycles. The developed algorithm and a webapp to browse the outcomes of the study are publicly available to serve as a resource for the scientific community.

ORGANISM(S): Mus musculus

PROVIDER: GSE135898 | GEO | 2020/12/03

REPOSITORIES: GEO

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Project description:Renal excretion of water and major electrolytes exhibits a significant circadian rhythm. This functional periodicity is believed to result, at least in part, from circadian changes in secretion/reabsorption capacities of the distal nephron and collecting ducts. Here, we studied the molecular mechanisms underlying circadian rhythms in the distal nephron segments, i.e. distal convoluted tubule (DCT) and connecting tubule (CNT) and, the cortical collecting duct (CCD). Temporal expression analysis performed on microdissected mouse DCT/CNT or CCD revealed a marked circadian rhythmicity in the expression of a large number of genes crucially involved in various homeostatic functions of the kidney. This analysis also revealed that both DCT/CNT and CCD possess an intrinsic circadian timing system characterized by robust oscillations in the expression of circadian core clock genes (clock, bma11, npas2, per, cry, nr1d1) and clock-controlled Par bZip transcriptional factors dbp, hlf and tef. The clock knockout mice or mice devoid of dbp/hlf/tef (triple knockout) exhibit significant changes in renal expression of several key regulators of water or sodium balance (vasopressin V2 receptor, aquaporin-2, aquaporin-4, M-oM-^AM-!ENaC). Functionally, the loss of clock leads to a complex phenotype characterized by partial diabetes insipidus, dysregulation of sodium excretion rhythms and a significant decrease in blood pressure. Collectively, this study uncovers a major role of molecular clock in renal function. Experiment Overall Design: We examined the temporal profiles of gene expression in mouse distal nephron segments and collecting ducts. The RNA was extracted from microdissected distal convoluted tubules and connecting tubules (DCT/CNT samples) or, cortical collecting ducts (CCD samples). Animals were sacrificed for microdissection every 4 hours, i.e. at ZT0, ZT4, ZT8, ZT12, ZT16 and ZT20 (ZT M-bM-^@M-^S Zeitgeber (circadian) time, indicates time of light-on as ZT0 and time of light-off as ZT12). The microarray hybridization was performed in duplicates on two pools of RNA composed of equivalent amounts of RNA prepared from five animals at each ZT time-point.

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Temporal profiles of gene expression in Cry1/2 KO, Bmal1 KO under night restricted feeding and ad libitum feeding regimen

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