CASyM winter school of Systems Medicine took place between March 29th and April 1st 2017 in Ljubljana, Slovenia and is entitled »The 3rd SysBioMed hands-on tutorial: Systems Medicine Approaches in Personalized Medicine«
1Centre for functional Genomics and Bio-Chips, Faculty of Medicine, University of Ljubljana, Slovenia
ICER is a product of gene named Crem. It is transcribed from an alternative P2 promoter and is a product of alternative splicing, therefore the majority of its RNA is not unique and is represented also in other Crem transcripts. For these reasons, studying of ICER is very challenging. The fact that Icer itself has more than one splicing isoform, makes the whole story even more complex. There are no specific antibodies available, qPCR assays have limited success, and no specific knock-out model has been generated. ICER is a transcription factor that is especially important in temporal events that happen as a response of cAMP signaling. It is a transcription repressor that binds CRE elements in promoters of different genes and competes with other CRE binding transcription factors like CREB, CREM etc. It is important in circadian and neuroendocrine system regulation. It regulates circadian synthesis of melatonin through repression of its rate-limiting enzyme arylalkylamine-N-acetyltransferase . ICER is important also for adrenal expression of different circadian genes, especially Per1  and Cyp17a1 methylation status . Another role of ICER was also found in apoptosis, since it was suggested that ICER down-regulates anti-apoptotic gene Bcl-2 . It is involved in reward learning and drug addiction through regulation of dopamine-β-hydroxylase and tyrosine hydroxylase. It is suggested that ICER could be involved in synthesis of dopamine and other catecholamines . ICER affects maturation of Th17 cells and is therefore important in autoimmune and inflammatory disorders . A broad scientific community would benefit from development of techniques that would allow ICER functional studies. We are dealing with different approaches that address this challenging topic. Our intention is to show ICER functionality with use of some indirect methods like antisense plasmids, siRNA transfections and more complex techniques like Crispr/Cas9 generation of knock-out cell line. We are in progress of generating Crispr/Cas9 knock-in of V5 tag to produce endogenous ICER-V5 tagged product. This would be especially useful in protein studies and would allow us to bypass the lack of specific ICER antibodies. References: 1. Borlikova G, Endo S (2009) Inducible cAMP Early Repressor (ICER) and Brain Functions. Mol. Neurobiol. 40, 73–86. 2. Zmrzljak UP, Korenčič A, Košir R, Goličnik M, Sassone-Corsi P, Rozman D (2013) Inducible cAMP Early Repressor Regulates the Period 1 Gene of the Hepatic and Adrenal Clocks. J. Biol. Chem. 288, 10318–10327. 3. Kosir R, Zmrzljak UP, Bele T, Acimovic J, Perse M, Majdic G, Prehn C, Adamski J, Rozman D (2012) Circadian expression of steroidogenic cytochromes P450 in the mouse adrenal gland--involvement of cAMP-responsive element modulator in epigenetic regulation of Cyp17a1. FEBS J 279, 1584–93. 4. Yoshida N, Comte D, Mizui M, Otomo K, Rosetti F, Mayadas TN, Crispín JC, Bradley SJ, Koga T, Kono M, Karampetsou MP, Kyttaris VC, Tenbrock K, Tsokos GC (2016) ICER is requisite for Th17 differentiation. Nat. Commun. 7, 12993.
2006 - University of Ljubljana, Faculty of Medicine, Center for Functional Genomics and Bio-chips.