Dataset Information

Bioinformatics analysis of transcriptional regulation of circadian genes in rat liver.

ABSTRACT:

Background

The circadian clock is a critical regulator of biological functions controlling behavioral, physiological and biochemical processes. Because the liver is the primary regulator of metabolites within the mammalian body and the disruption of circadian rhythms in liver is associated with severe illness, circadian regulators would play a strong role in maintaining liver function. However, the regulatory structure that governs circadian dynamics within the liver at a transcriptional level remains unknown. To explore this aspect, we analyzed hepatic transcriptional dynamics in Sprague-Dawley rats over a period of 24 hours to assess the genome-wide responses.

Results

Using an unsupervised consensus clustering method, we identified four major gene expression clusters, corresponding to central carbon and nitrogen metabolism, membrane integrity, immune function, and DNA repair, all of which have dynamics which suggest regulation in a circadian manner. With the assumption that transcription factors (TFs) that are differentially expressed and contain CLOCK:BMAL1 binding sites on their proximal promoters are likely to be clock-controlled TFs, we were able to use promoter analysis to putatively identify additional clock-controlled TFs besides PARF and RORA families. These TFs are both functionally and temporally related to the clusters they regulate. Furthermore, we also identified significant sets of clock TFs that are potentially transcriptional regulators of gene clusters.

Conclusions

All together, we were able to propose a regulatory structure for circadian regulation which represents alternative paths for circadian control of different functions within the liver. Our prediction has been affirmed by functional and temporal analyses which are able to extend for similar studies.

SUBMITTER: Nguyen TT

PROVIDER: S-EPMC3987685 | biostudies-literature | 2014 Mar

REPOSITORIES: biostudies-literature

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Publications

Bioinformatics analysis of transcriptional regulation of circadian genes in rat liver.

Nguyen Tung T TT Mattick John S A JS Mattick John S A JS Yang Qian Q Orman Mehmet A MA Ierapetritou Marianthi G MG Berthiaume Francois F Androulakis Ioannis P IP

BMC bioinformatics 20140325

<h4>Background</h4>The circadian clock is a critical regulator of biological functions controlling behavioral, physiological and biochemical processes. Because the liver is the primary regulator of metabolites within the mammalian body and the disruption of circadian rhythms in liver is associated with severe illness, circadian regulators would play a strong role in maintaining liver function. However, the regulatory structure that governs circadian dynamics within the liver at a transcriptional ...[more]

PMID: 24666587

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Project description:Circadian rhythms are 24 hour oscillations in many behavioural, physiological, cellular and molecular processes that are controlled by an endogenous clock which is entrained to environmental factors including light, food and stress. Transcriptional analyses of circadian patterns demonstrate that genes showing circadian rhythms are part of a wide variety of biological pathways.Pathway activity method can identify the significant pattern of the gene expression levels within a pathway. In this method, the overall gene expression levels are translated to a reduced form, pathway activity levels, via singular value decomposition (SVD). A given pathway represented by pathway activity levels can then be as analyzed using the same approaches used for analyzing gene expression levels. We propose to use pathway activity method across time to identify underlying circadian pattern of pathways.We used synthetic data to demonstrate that pathway activity analysis can evaluate the underlying circadian pattern within a pathway even when circadian patterns cannot be captured by the individual gene expression levels. In addition, we illustrated that pathway activity formulation should be coupled with a significance analysis to distinguish biologically significant information from random deviations. Next, we performed pathway activity level analysis on a rich time series of transcriptional profiling in rat liver. The over-represented five specific patterns of pathway activity levels, which cannot be explained by random event, exhibited circadian rhythms. The identification of the circadian signatures at the pathway level identified 78 pathways related to energy metabolism, amino acid metabolism, lipid metabolism and DNA replication and protein synthesis, which are biologically relevant in rat liver. Further, we observed tight coordination between cholesterol biosynthesis and bile acid biosynthesis as well as between folate biosynthesis, one carbon pool by folate and purine-pyrimidine metabolism. These coupled pathways are parts of a sequential reaction series where the product of one pathway is the substrate of another pathway.Rather than assessing the importance of a single gene beforehand and map these genes onto pathways, we instead examined the orchestrated change within a pathway. Pathway activity level analysis could reveal the underlying circadian dynamics in the microarray data with an unsupervised approach and biologically relevant results were obtained.

Project description:BackgroundFerroptosis is a form of iron-dependent cell death with increased free iron and massive lipid peroxidation. The discovery of ferroptosis offers insights into hepatocellular carcinoma (HCC) treatment. However, post-transcriptional regulation mechanisms of ferroptosis in HCC remain to be elucidated. The present study explored ferroptosis-related genes and their post-transcriptional regulation mechanisms in HCC.MethodsA ferroptosis score was computed in The Cancer Genome Atlas (TCGA) cohort via gene set variation analysis (GSVA), and ferroptosis-related genes were screened by differential expression and correlation analyses. CircRNA/miRNA-mediated ferroptosis-related genes were predicted, and associations of ferroptosis-related genes with m1A/m5C/m6A regulators were analyzed. Immune cell infiltrations were inferred via CIBERSORT. NUDCD1 expression was examined in L-02, SMMC7721, and HepG2 cells via real time quantitative polymerase chain reaction (RT-qPCR) and western blots. After NUDCD1 was silenced, cell viability, glutathione peroxidase 4 (GPX4) and ferritin heavy chain 1 (FTH1) expression, and oxidized glutathione/glutathione (GSSG/GSH) and glutathione (GSH) levels were detected in SMMC7721 and HepG2 cells.ResultsThe ferroptosis score was linked to poor overall survival (OS) of HCC, which was independent of other clinicopathological parameters. Ten ferroptosis-related genes were determined, namely UGT1A6, ATP6V1C1, MAFG, NUDCD1, PPP1R1A, TSKU, CTSB, AIFM2, CTSA, and CTNND2, which were post-transcriptionally regulated by circRNA/miRNA and m1A/m5C/m6A modifications in HCC. Most were significantly linked with most immune cell compositions within the immune microenvironment, and contributed to undesirable clinical outcomes. NUDCD1 was up-regulated in HCC cells, and its loss facilitated the ferroptosis of HCC cells.ConclusionsOverall, our findings determined ferroptosis-related genes post-transcriptionally regulated by circRNA/miRNA and m1A/m5C/m6A RNA modifications, and experiments demonstrated that loss of NUDCD1 may facilitate the ferroptosis of HCC cells, which provides novel insights into the regulatory mechanisms of ferroptosis in HCC.

Dataset Information

Bioinformatics analysis of transcriptional regulation of circadian genes in rat liver.

Background

Results

Conclusions

Publications

Bioinformatics analysis of transcriptional regulation of circadian genes in rat liver.

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