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Ljubljana, Slovenia

Kosir R.,University of Ljubljana | Kosir R.,Diagenomi Ltd | Juvan P.,University of Ljubljana | Perse M.,University of Ljubljana | And 6 more authors.

The essential role of the Crem gene in normal sperm development is widely accepted and is confirmed by azoospermia in male mice lacking the Crem gene. The exact number of genes affected by Crem absence is not known, however a large difference has been observed recently between the estimated number of differentially expressed genes found in Crem knock-out (KO) mice compared to the number of gene loci bound by CREM. We therefore re-examined global gene expression in male mice lacking the Crem gene using whole genome transcriptome analysis with Affymetrix microarrays and compared the lists of differentially expressed genes from Crem-/- mice to a dataset of genes where binding of CREM was determined by Chip-seq. We determined the global effect of CREM on spermatogenesis as well as distinguished between primary and secondary effects of the CREM absence. We demonstrated that the absence of Crem deregulates over 4700 genes in KO testis. Among them are 101 genes associated with spermatogenesis 41 of which are bound by CREM and are deregulated in Crem KO testis. Absence of several of these genes in mouse models has proven their importance for normal spermatogenesis and male fertility. Our study showed that the absence of Crem plays a more important role on different aspects of spermatogenesis as estimated previously, with its impact ranging from apoptosis induction to deregulation of major circadian clock genes, steroidogenesis and the cell-cell junction dynamics. Several new genes important for normal spermatogenesis and fertility are down-regulated in KO testis and are therefore possible novel targets of CREM. © 2012 Kosir et al. Source

Naik A.,University of Ljubljana | Kosir R.,University of Ljubljana | Kosir R.,Diagenomi Ltd | Rozman D.,University of Ljubljana

Non-alcoholic fatty liver disease (NAFLD) is the most predominant liver disease worldwide and hepatic manifestation of the metabolic syndrome. Its histology spectrum ranges from steatosis, to steatohepatitis (NASH) that can further progress to cirrhosis and hepatocellular carcinoma (HCC). The increasing incidence of NAFLD has contributed to rising numbers of HCC occurrences. NAFLD progression is governed by genetic susceptibility, environmental factors, lifestyle and features of the metabolic syndrome, many of which overlap with HCC. Gene expression profiling and genome wide association studies have identified novel disease pathways and polymorphisms in genes that may be potential biomarkers of NAFLD progression. However, the multifactorial nature of NAFLD and the limited number of sufficiently powered studies are among the current limitations for validated biomarkers of clinical utility. Further studies incorporating the links between circadian regulation and hepatic metabolism might represent an additional direction in the search for predictive biomarkers of liver disease progression and treatment outcomes copy; 2013 Elsevier Inc. Source

Zmrzljak U.P.,Institute of Biochemistry | Zmrzljak U.P.,Institute of Oncology | Korencic A.,Institute of Biochemistry | Kosir R.,Institute of Oncology | And 4 more authors.
Journal of Biological Chemistry

Light, restricted feeding, and hormonal inputs may operate as time givers (zeitgebers) for the circadian clock within peripheral organs through the activation of tissue-specific signaling cascades. cAMP signaling through CREM (cAMP-responsive element modulator) and its variant ICER (inducible cAMP early repressor) is linked to the circadian regulation of pineal melatonin synthesis, although little is known about its influence in other organs.Weperformed experiments in the absence of light and feeding-time cues to test which core clock genes are controlled by CREM/ICER in the liver and adrenal gland. In vivo, Crem loss-of-function mutation resulted in fine-tuning of all measured adrenal clock genes (Per1/2/3, Cry1/2, Bmal1, and Rev-erb), whereas only Per1 and Cry1 were affected in the liver. Icer expression was circadian in the adrenal gland, with peak gene expression at zeitgeber 12 and the highest protein levels at zeitgeber 20. The expression of both Icer and Per1 genes responded to cAMP stimuli in an immediate-early fashion. In immortal cells, forskolin induced expression of Per1 after 2 h, and de novo protein synthesis led to Per1 attenuation. We show that the de novo synthesized protein responsible for Per1 attenuation is ICER. Indeed, Per1 expression is up-regulated in cells ectopically expressing antisense Icer, and mobility shift experiments identified ICER binding to cAMP-responsive elements of the Per1 promoter. We propose that ICER acts as a noise filter for different signals that could affect transcription in the adrenal gland. Because ICER is an immediate-early repressor, the circadian nature of adrenal Icer expression could serve a role in a time-dependent gating mechanism. © 2013 by The American Society for Biochemistry and Molecular Biology, Inc. Source

Kosir R.,University of Ljubljana | Kosir R.,Diagenomi Ltd | Spaninger K.,University of Ljubljana | Spaninger K.,Diagenomi Ltd | Rozman D.,University of Ljubljana

The biochemical basis of the mammalian circadian clock can be described by transcriptional-translational feedback loops with a period of about 24 h. Crucial endogenous factors are under circadian control (i.e., body temperature, blood pressure, hormone secretion and metabolite levels). Also, drug metabolism, including phases I-III and the drug-responsive nuclear receptors, is controlled by the clock. Disturbances in circadian rhythm in humans can lead to pathologies, which is exemplified by increased cancer risk in long-term shift workers. On the other hand, best tolerability of drugs with minimum side effects can be achieved if the timing of drug treatment is synchronized with the patients' individual clock. The aim of this review is to underline the importance of accepting the individuals' endogenous clock which can contribute to personalized, patient-friendly optimization of drug therapies. © 2013 IUBMB Life. Source

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