Circadian modulation of hepatic transcriptome in transgenic rats expressing human growth hormone

Medicinal Safety Research Laboratories, Daiichi Sankyo Co., Ltd., Fukuroi, Shizuoka, Japan.
The Journal of Toxicological Sciences (Impact Factor: 1.29). 10/2010; 35(5):673-85. DOI: 10.2131/jts.35.673
Source: PubMed


The secretory profile of growth hormone (GH) is sexually dimorphic in rats. In male transgenic (TG) rats expressing human GH (hGH) that we generated, the circulating levels of both hGH and endogenous GH are flattened with no male-type pulsatility. To elucidate the regulatory role of episodic GH profile on the liver, the hepatic transcriptome of male TG rats at the middle of the light and dark phases was characterized by genome-wide analyses as compared with that of male wild-type (WT) rats. Transcripts commonly up- or down-regulated regardless of the lighting conditions in TG rats were mainly enriched in the metabolism of xenobiotics. In TG rats, the gene expression profile was functionally feminized, verifying that the sexually dimorphic profile of GH rather than genetic sexuality is a stronger sex-determining factor on the hepatic transcriptome. The common transcripts which fluctuated during the day in both TG and WT rats were enriched in circadian rhythm signaling, and physiological rhythmicity was considered to be finely interconnected with liver metabolism via sexually dimorphic GH secretion. In contrast, some genes were differentially regulated in TG rats at only one of two time points measured, and others were fluctuated daily in only one genotype. In particular, some genes involved in the GH signaling pathway were included, suggesting the signal transduction is circadian-modulated depending upon the GH profile. Our transcriptome analyses clarified the regulatory role of episodic GH profile on the liver and strengthen the functional link between sexually dimorphic GH secretion, liver metabolism, and its circadian regulation.

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Available from: Jun Hirao, Mar 03, 2015
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    • "In addition, many other genes related to primary metabolism and are known to oscillate in a circadian manner e.g. bmal, gcjr, dhtkd1, cth, gaba, gldc, kynu, akr1c18[22], chka and agxt[23]. "
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    ABSTRACT: 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. 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. 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.
    Full-text · Article · Mar 2014 · BMC Bioinformatics
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    • "We have shown that sexually dimorphic GH pulsatility is responsible for the circadian rhythms of hepatic ACD activities (Furukawa et al., 1999c). In addition, male-predominant P450 subfamilies such as Cyp2c11 and Cyp3a2 are known to be under the control of GH secretion (Ahluwalia et al., 2004; Hirao et al., 2010). Our transcriptome analysis, however, indicated that male-predominant P450 genes were not expressed in a circadian fashion. "
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    ABSTRACT: The present study was designed to fully uncover sex and circadian modulatory effects on rat liver. Hepatic transcriptome analyses were performed at 4 hr intervals of a day-night cycle using young adult male and female rats. Sexually dimorphic genes, which were identified by a cross-sex comparison of time series data, included representative sex-predominant genes such as male- or female-predominant cytochrome P450 subfamilies (Cyp2c11, Cyp2c12, Cyp2c13, and Cyp3a2), sulfotransferases, and glutathione S-transferase Yc2. The identified sexually dimorphic genes were over-represented in the metabolism of retinols, xenobiotics, linoleic acids, or androgen and estrogen, or bile acid biosynthesis. Furthermore, transcription factor targets modeling suggested that transcription factors SP1, hepatocyte nuclear factor 4-alpha (HNF4-alpha), and signal transducer and activator of transcription 5b (STAT5b) serve as core nodes in the regulatory networks. On the other hand, Fourier transform analyses extracted universal circadian-regulated genes in both sexes. The circadian-regulated genes included clock or clock-controlled genes such as aryl hydrocarbon receptor nuclear translocator-like (Arntl), period homolog 2 (Per2), and D site albumin promoter binding protein (Dbp). The extracted cyclic genes were over-represented in major tissue activities, e.g. the urea cycle and the metabolism of amino acids, fatty acids, or glucose, indicating that the major liver functions are under circadian control. The transcription factor targets modeling suggested that transcription factors SP1, HNF4-alpha, and c-Myc proto-oncogene protein (c-MYC) serve as major hubs in the circadian-regulatory gene networks. Interestingly, transcription factors SP1 and HNF4-alpha are likely to orchestrate not only sexually dimorphic, but also circadian-regulated genes even though each criterion was rather mutually exclusive. This suggests the cross-talk between those regulations. Sexual dimorphism is likely to interact with circadian rhythmicity via overlapping gene regulatory networks on rat liver.
    Full-text · Article · Feb 2011 · The Journal of Toxicological Sciences

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