cAMP Response Element Modulator Research Articles

The cAMP response element modulator (CREM) regulates TH2 mediated inflammation.

A characteristic feature of allergic diseases is the appearance of a subset of CD4+ cells known as TH2 cells, which is controlled by transcriptional and epigenetic mechanisms. We aimed to analyze the role of CREM, a known transcriptional activator of T cells, with regard to TH2 responses and allergic diseases in men and mice. Here we demonstrate that T cells of asthmatic children and PBMCs of adults with atopy express lower mRNA levels of the transcription factor CREM compared to cells from healthy controls. CREM deficiency in murine T cells results in enhanced TH2 effector cytokines in vitro and in vivo and CREM-/- mice demonstrate stronger airway hyperresponsiveness in an OVA-induced asthma model. Mechanistically, both direct CREM binding to the IL-4 and IL-13 promoter as well as a decreased IL-2 dependent STAT5 activation suppress the TH2 response. Accordingly, mice selectively overexpressing CREMα in T cells display decreased TH2 type cytokines in vivo and in vitro, and are protected in an asthma model. Thus, we provide evidence that CREM is a negative regulator of the TH2 response and determines the outcome of allergic asthma.

Exercise-induced differential changes in gene expression among arterioles of skeletal muscles of obese rats.

Using next-generation, transcriptome-wide RNA sequencing (RNA-Seq) technology we assessed the effects of exercise training on transcriptional profiles in skeletal muscle arterioles isolated from the soleus and gastrocnemius muscles of Otsuka Long Evans Tokushima Fatty (OLETF) rats that underwent an endurance exercise training program (EX; n = 13), interval sprint training program (SPRINT; n = 14), or remained sedentary (Sed; n = 12). We hypothesized that the greatest effects of exercise would be in the gastrocnemius arterioles. Results show that EX caused the largest number of changes in gene expression in the soleus and white gastrocnemius 2a arterioles with little to no changes in the feed arteries. In contrast, SPRINT caused substantial changes in gene expression in the feed arteries. IPA canonical pathway analysis revealed 18 pathways with significant changes in gene expression when analyzed across vessels and revealed that EX induces increased expression of the following genes in all arterioles examined: Shc1, desert hedgehog protein (Dhh), adenylate cyclase 4 (Adcy4), G protein binding protein, alpha (Gnat1), and Bcl2l1 and decreased expression of ubiquitin D (Ubd) and cAMP response element modulator (Crem). EX increased expression of endothelin converting enzyme (Ece1), Hsp90b, Fkbp5, and Cdcl4b in four of five arterioles. SPRINT had effects on expression of Crem, Dhh, Bcl2l1, and Ubd that were similar to EX. SPRINT also increased expression of Nfkbia, Hspa5, Tubb 2a and Tubb 2b, and Fkbp5 in all five arterioles and increased expression of Gnat1 in all but the soleus second-order arterioles. Many contractile and/or structural protein genes were increased by SPRINT in the gastrocnemius feed artery, but the same genes exhibited decreased expression in red gastrocnemius arterioles. We conclude that training-induced changes in arteriolar gene expression patterns differ by muscle fiber type composition and along the arteriolar tree.

Interleukin-2 treatment reverses effects of cAMP-responsive element modulator α-over-expressing T cells in autoimmune-prone mice.

Systemic autoimmune diseases, such as systemic lupus erythematosus (SLE), are often characterized by a failure of self-tolerance and result in an uncontrolled activation of B cells and effector T cells. Interleukin (IL)-2 critically maintains homeostasis of regulatory T cells (T(reg)) and effector T cells in the periphery. Previously, we identified the cAMP-responsive element modulator α (CREMα) as a major factor responsible for decreased IL-2 production in T cells from SLE patients. Additionally, using a transgenic mouse that specifically over-expresses CREMα in T cells (CD2CREMαtg), we provided in-vivo evidence that CREMα indeed suppresses IL-2 production. To analyse the effects of CREMα in an autoimmune prone mouse model we introduced a Fas mutation in the CD2CREMαtg mice (FVB/Fas(-/-) CD2CREMαtg). Overexpression of CREMα strongly accelerated the lymphadenopathy and splenomegaly in the FVB/Fas(-/-) mice. This was accompanied by a massive expansion of double-negative (DN) T cells, enhanced numbers of interferon (IFN)-γ-producing T cells and reduced percentages of T(regs). Treatment of FVB/Fas(-/-) CD2CREMαtg mice with IL-2 restored the percentage of T(regs) and reversed increased IFN-γ production, but did not affect the number of DNTs. Our data indicate that CREMα contributes to the failure of tolerance in SLE by favouring effector T cells and decreasing regulatory T cells, partially mediated by repression of IL-2 in vivo.

The role of peripheral Rho-associated protein kinase in acupuncture analgesia

Purpose: CREM (cyclic AMP-responsive element modulator) gene is essential for spermatogenesis, as it is necessary in differentiation of spermatids into sperm. In this study, to investigate the effect of Epimedii Herba (EH) on the sperm functions and the CREM transcription factor expressions in cyclophosphamide-treated mouse testes, C57BL/c mice were divided into five groups, the normal group, CP only-treated group and EH with CP (100, 500, 1000mg/kg of EH and 100mg/kg of CP) treated group for five weeks. Methods: We performed semi-quantitive PCR and western blot analysis for the examination of the CREM expression and analyzed sperm parameters using CASA system. Results: In our results, EH showed protective effect on CP induced reproductive toxicity in male mice by recovering sperm count, motility. CREM expression increased in EH treated groups at 500mg/kg concentration than that of control group (83.8%; p<0.01 vs. 71.5%; p<0.05, respectively). Conclusion:Our results suggest that EH plays an important role in male fertility, and it could be applied for clinical use in infertility treatment. Contact: Kyujin Chung, hykim0927@naver.com

ICER controls Th17 cell differentiation and autoimmune pathology (IRM15P.600)

Abstract Inducible cAMP early repressor (ICER) is a splice variant of cAMP-responsive element modulator (CREM). Because ICER lacks transcriptional activation domains, ICER acts as a repressor of various genes involved in immune cell function and inhibits T cell activation by suppressing the induction of pro-inflammatory cytokines including IL-2. However, little is known about ICER involvement in IL-17 production and Th17 differentiation. Culture of murine naïve CD4 T cells under Th17 skewing conditions showed surprisingly high expression of ICER indicating and important role in these cells. T cells from animals in which the CREM gene had been deleted were cultured under these conditions, which revealed less IL-17 than T cells from CREM sufficient mice. Because ICER induction is abrogated in T cells from STAT3-deficient mice, we considered the possibility that IL6-STAT3 signaling plays a crucial role in ICER induction in Th17 T cells. We expanded our observations in vivo. We induced experimental anti-glomerular basement membrane antibody glomerulonephritis (AIGN) and experimental autoimmune encephalomyelitis model (EAE) in CREM-deficient and sufficient animals and found that CREM-deficient had diminished nephritis and encephalomyelitis. Collectively, our results suggest that the transcription factor ICER supports Th17 differentiation and promotes Th17-dependent autoimmune pathology.

Effects of Rosae Laevigatae Fructus on the cyclic AMP response element modulator (CREM) expression during spermatogenesis

only-treated group and several concentrations of WSH and CP (100mg/kg of CP) treated group for the same period. Results: WSH has effect on absolute and relative testes weight, sperm count, sperm motility and serum testosterone level in CP treated mice. CP and 100, 500, 1000mg/kg of WSH treatment groups significantly increased the testosterone levels by 144.38, 142.73, 154.96% compared to the only-treated group in the mouse serum. Conclusion: Our results suggest that WSH plays an important role in the male reproductive function by improving serum testosterone level. Contact: Byung Chun Park, kakurakuka@hanmail.net

Epimedii Herba enhances reproductive function through induction of cyclic AMP-responsive element modulator expression in infertile male mice

Epimedii Herba enhances reproductive function through induction of cyclic AMP-responsive element modulator expression in infertile male mice

Transcription factor cAMP response element modulator (Crem) restrains Pdgf-dependent proliferation of vascular smooth muscle cells in mice.

Transcription factors of the cAMP response element-binding protein (Creb)/cAMP response element modulator (Crem) family were linked to the switch from a contractile to a proliferating phenotype in vascular smooth muscle cells (VSMCs). Here, we analyzed the vascular function of Crem in mice with a global inactivation of Crem (Crem−/−). CRE-mediated transcriptional activity was enhanced in primary Crem−/− VSMCs under nonstimulated conditions and under stimulation with Forskolin and platelet-derived growth factor (Pdgf) whereas stimulation with nitric oxide or cGMP showed no effect. This elevated CRE-mediated transcriptional activity as a result of Crem inactivation did not alter aortic contractility or fractions of proliferating or apoptotic aortic VSMCs in situ, and no impact of Crem inactivation on the development of atherosclerotic plaques was observed. Crem−/− mice exhibited an increased neointima formation after carotid ligation associated with an increased proliferation of VSMCs in the carotid media. Pdgf-stimulated proliferation of primary aortic Crem−/− VSMCs was increased along with an upregulation of messenger RNA (mRNA) levels of Pdgf receptor, alpha polypeptide (Pdgfra), cyclophilin A (Ppia), the regulator of G-protein signaling 5 (Rgs5), and Rho GTPase-activating protein 12 (Arhgap12). Taken together, our data reveal the inhibition of Pdgf-stimulated proliferation of VSMCs by repressing the Pdgf-stimulated CRE-mediated transcriptional activation as the predominant function of Crem in mouse vasculature suggesting an important role of Crem in vasculoproliferative diseases.Electronic supplementary materialThe online version of this article (doi:10.1007/s00424-014-1652-6) contains supplementary material, which is available to authorized users.

The transcription factor crem-αlpha regulates inflammatory T cell subsets in juvenile idiopathic arthritis

The cAMP response element (CRE) modulator (CREM)α binds to promoters of genes with CREs and regulates transcription via a chromatin-dependent mechanism. CREMα is important for the T cell pathophysiology of SLE by suppression of IL-2 and CD3ζ but enhancement of IL-17 transcription. Juvenile idiopathic arthritis (JIA) is an autoimmune disease of unknown origin. Th17 cells have a pathogenic role in arthritis and are not controlled by local FoxP3+ regulatory T cells (Tregs). Pathogenic T cells in the inflamed joints of JIA patients have enhanced expression of IL-17, IFN-γ and CD161. CD161+ CD4+ cells also contain FoxP3+ cells that produce proinflammatory cytokines. A higher frequency of CD161 Tregs appears to associate with more severe disease in JIA, a fact which might contribute to the failure by Treg to suppress ongoing inflammation.

CREM variants rs4934540 and rs2295415 conferred susceptibility to nonobstructive azoospermia risk in the Chinese population.

To evaluate the association of variants related to spermatogenesis with susceptibility to Chinese idiopathic nonobstructive azoospermia (NOA), seventeen tag single-nucleotide polymorphisms (SNPs) in CREM, ACT, KIF17b, and SPAG8 were analyzed in 361 NOA patients and 368 controls by Sequenom iplex technology. The results showed that two CREM SNPs, rs4934540 and rs22954152, were significantly associated with NOA and played protective roles against the disease (P value with Bonferroni correction = 0.00017, odds ratio [OR] = 0.624 and P = 0.012, OR = 0.686, respectively). Haplotype analysis of CREM gene variants suggested that haplotype CGTG of the SNPs, rs4934540, rs2295415, rs11592356, and rs1148247, exhibited significant protective effect against the occurrence of NOA (P = 0.001, OR = 0.659). The haplotype TATG conferred a significantly increased risk of NOA (P = 0.011, OR = 1.317). Furthermore, making use of quantitative RT-PCR, we demonstrated that relative mRNA expression of CREM in NOA patients with maturation arrest was only one-third of that in the controls with normal spermatogenesis (P < 0.0001). Our findings indicated that the polymorphisms of CREM gene were associated with NOA in the Chinese population and low CREM expression might be involved in the pathogenesis of spermatogenesis maturation arrest.

The transcription factor CREMalpha regulates inflammatory T cell subsets in juvenile idiopathic arthritis (BA13P.115)

Abstract The cAMP response element (CRE) modulator (CREM)α binds to genes promoters with CREs and regulates transcription via a chromatin-dependent mechanism. CREMα is important for the T cell pathophysiology of SLE suppressing IL-2 and CD3ζ transcription, but enhances IL-17. Juvenile idiopathic arthritis (JIA) is an autoimmune disease of unknown origin. Th17 cells have a pathogenic role in arthritis and are not controlled by local FoxP3+ regulatory T cells (Tregs). Pathogenic T cells in the inflamed joints of JIA patients have enhanced expression of IL-17, IFNgamma and CD161. CD161+ CD4+ cells also contain FoxP3+ cells that produce proinflammatory cytokines. We observed enhanced CREM expression in JIA patient synovial fluid (SF) T cells and also after culture of healthy donor PBMCs with JIA SF. We furthermore found enhanced expression of CREM in CD4+CD161+ and in CD4+FoxP3+CD161+ cells, which produce inflammatory cytokines. Vice versa Helios+FoxP3+ cells, which are characteristically stable Tregs and do not express inflammatory cytokines, had lower levels of CREM. JIA SF induced IFNgamma, IL-17 and FoxP3 in T cells during incubation, which could be abrogated by CREM siRNA transfection. Within the FoxP3+ population, CREM siRNA reduced CD161+FoxP3+ cells but not Helios+FoxP3+ cells. We thus suggest CREMα overexpression in T cells contributes to T cell pathophysiology in JIA by regulating percentages of inflammatory CD4+ IL-17+ cells, as well as inflammatory CD161+FoxP3+ cells.

T helper 9 (Th9) cellular proliferation and cytokine production is regulated by cAMP responsive element modulator (Crem) (HYP7P.289)

Abstract Th9 cells, a CD4+ T cell subset characterized by their robust production of interleukin (IL)-9, can promote allergic inflammation in mice and are associated with atopic disease in humans. Because it might provide targets for therapeutic intervention, it is important to understand the molecular controls governing overall Th9 development and their subsequent effector function. To understand the Th9 transcriptional profile, we recently performed microarray analysis to highlight gene expression enriched in Th9 cells compared to other Th subsets. Crem, which expresses a basic leucine zip domain protein with roles in activating and repressing genes, was among a number of genes with increased expression in Th9 cells. Analysis of mRNA and protein expression among in vitro differentiated Th subsets confirmed Crem was enriched in Th9 cells compared to other subsets. Interestingly, ectopic expression of Crem in Th9 cells repressed their capacity to produce IL-9 upon CD3 re-stimulation while promoting overall cellular proliferation. Crem ectopic expression also promoted cellular expansion in other cultured Th subsets. Conversely, acute siRNA knockdown of Crem mRNA in Th9 differentiated cells resulted in reduced cellular proliferation and enhanced IL-9 production upon CD3 restimulation. Therefore, Crem potentially serves a role in modifying Th9 effector activities upon T cell receptor signaling during allergic disease.

In Vitro knock out of Inducible Cyclicamp Early Repressor(ICER) in zebrafish cell lines through the use of the CrispR/Cas9 system (LB530)

ICER is a dominant negative transcriptional regulator induced by cAMP and it binds to CREB or CREM in order to repress cAMP‐mediated gene expression. Inhibin alpha, Inha, has been shown to regulate gonadal stromal cell proliferation and suppress tumor activity. The multi‐functions of ICER: as a neuronal plasticity, tumor suppressor, regulator of apoptosis, and etc., have led to the characterization of the relevant gene in various organisms like Homo‐sapiens (humans), Mus, musculus (mouse) and Gallus gallus (chicken) (NCBI). Recently the ICER sequence had been continuously expressed in Danio rerio (zebra fish) through use of the vectors pFlag and TOPO. ICER, which is regulated by the signal path of cAMP, represses the expression of CREM gene is its isoforms. This fact proves to be a favorable influence in the regulation of cancer. Using zebrafish as models, we utilized the Clustered Regular Interspersed Short Palindromic Repeats (CRISPR) system with the Cas9 in order to knock out the ICER promoter gene. These were done in two cell lines, embryo fibroblast and tailfin. Our assay results showed the disappearance of the ICER gene, and we will do further experimentation on our cell lines.

MP66-05 OXIDATIVE STRESS PROTEINS IDENTIFIED IN HUMAN SPERMATOZOA BY PROTEOMIC AND BIOINFORMATIC ANALYSIS

You have accessJournal of UrologyInfertility: Basic Research, Physiology & Pathophysiology1 Apr 2014MP66-05 OXIDATIVE STRESS PROTEINS IDENTIFIED IN HUMAN SPERMATOZOA BY PROTEOMIC AND BIOINFORMATIC ANALYSIS Rakesh Sharma, Ashok Agarwal, Damayanthi Durairajanayagam, Zhihong Cui, Ahmet Ayaz, and Edmund Sabanegh Rakesh SharmaRakesh Sharma More articles by this author , Ashok AgarwalAshok Agarwal More articles by this author , Damayanthi DurairajanayagamDamayanthi Durairajanayagam More articles by this author , Zhihong CuiZhihong Cui More articles by this author , Ahmet AyazAhmet Ayaz More articles by this author , and Edmund SabaneghEdmund Sabanegh More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2014.02.2052AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Oxidative stress is associated with male infertility. Understanding the protein profile of spermatozoa is essential for better diagnosis of male infertility. The aim of the present study was to examine the effect of high ROS production on the proteomic profile and cellular distribution of spermatozoal proteins. METHODS Seminal ejaculates from 52 subjects (32 infertile men and 20 healthy men) were classified as ROS+ or ROS- and evaluated for their proteomic profile. Samples were pooled and subjected to LC-MS/MS analysis. Differentially (over- or under-) expressed proteins were identified and further categorized as common and unique. Functional bioinformatic analysis was done using both publicly available Gene Ontology annotations, as well as proprietary databases such as Ingenuity Pathway Analysis (IPATM) and MetacoreTM to identify the differentially affected processes, pathways, interactions and cellular distribution of the proteins. RESULTS Of 74 identified proteins, 47 were over-expressed and 27 under-expressed compared to the ROS- group. Fifteen of the 74 proteins were 2-fold differentially expressed in the ROS+ group, of which 10 were overexpressed and 5 underexpressed. Most of the differentially expressed proteins were localized to the cytoplasmic and intracellular regions. In the ROS+ group, there was increased expression of histone cluster 1H2ba, mitochondrial malate dehydrogenase precursor, transglutaminase 4, glutathione peroxidase 4 isoform A precursor, glutamine synthetase and heat shock proteins. Androgen receptor was identified as one of the topmost regulators in the ROS+ group with 21 differentially expressed proteins interacting with the receptor. cAMP responsive element modulator (CREM) signaling, which plays an important role in male fertility, was one of the key pathways associated with the differentially expressed proteins. CONCLUSIONS We identified various proteins that are implicated in a multitude of functions associated with response and management of oxidative stress. The increased expression of proteins in the ROS+ group suggests some of these proteins may serve as potential biomarkers of oxidative stress. Alterations reported in our study may help explain pathways leading to the altered semen phenotype, especially in men exhibiting oxidative stress. © 2014FiguresReferencesRelatedDetails Volume 191Issue 4SApril 2014Page: e742 Advertisement Copyright & Permissions© 2014MetricsAuthor Information Rakesh Sharma More articles by this author Ashok Agarwal More articles by this author Damayanthi Durairajanayagam More articles by this author Zhihong Cui More articles by this author Ahmet Ayaz More articles by this author Edmund Sabanegh More articles by this author Expand All Advertisement Advertisement PDF DownloadLoading ...

CaMK4-dependent activation of AKT/mTOR and CREM-α underlies autoimmunity-associated Th17 imbalance

Tissue inflammation in several autoimmune diseases, including SLE and MS, has been linked to an imbalance of IL-17-producing Th (Th17) cells and Tregs; however, the factors that promote Th17-driven autoimmunity are unclear. Here, we present evidence that the calcium/calmodulin-dependent protein kinase IV (CaMK4) is increased and required during Th17 cell differentiation. Isolation of naive T cells from a murine model of lupus revealed increased levels of CaMK4 following stimulation with Th17-inducing cytokines but not following Treg, Th1, or Th2 induction. Furthermore, naive T cells from mice lacking CaMK4 did not produce IL-17. Genetic or pharmacologic inhibition of CaMK4 decreased the frequency of IL-17-producing T cells and ameliorated EAE and lupus-like disease in murine models. Inhibition of CaMK4 reduced Il17 transcription through decreased activation of the cAMP response element modulator α (CREM-α) and reduced activation of the AKT/mTOR pathway, which is known to enhance Th17 differentiation. Importantly, silencing CaMK4 in T cells from patients with SLE and healthy individuals inhibited Th17 differentiation through reduction of IL17A and IL17F mRNA. Collectively, our results suggest that CaMK4 inhibition has potential as a therapeutic strategy for Th17-driven autoimmune diseases.

The Effects of &lt;em&gt;Anethum graveolens&lt;/em&gt; L. Seeds on the Male Reproductive Functions and CREM Gene Expression in the Testis of Rat

It is undeniable that the increasing of the population in the developing countries is an anxiety, therefore finding safe and effective contraceptive materials can be very useful. The aim of this study was to investigate the effects of <em>Anethum graveolens</em> L. on the reproductive system of male rat and CREM gene expression in testis of rat. Animals were randomly divided into two groups of control (treated with normal salin for the period of 56 days, n = 8) and experimental (treated with 150 mg/kg/day of <em>Anethum graveolens</em> extract for 56 days, n = 8). RT-PCR and histological studies, hormonal assay and sperm analysis were carried out for evaluating of extract on reproductive function of rat. Results indicated no significant differences between body weights of control and experimental groups. Sperm counts and motility were reduced however there was an increase sperm abnormality by applying of extract. Indeed existence of disorganized germinal epitheliums, degeneration, necrotic cells in some of seminiferous tubules and lower concentration of sperms in the center of seminiferous tubules of experimental group was noticeable. Results also showed reduction in the diameter of seminiferous tubules of experimental groups comparing with control groups. Administration of extract caused a significant decline in the plasma level of testosterone. Our RT-PCR data revealed that CREM mRNA levels decreased significantly in testes from the experimental group in compared to control group. In conclusion <em>Anethum graveolens</em> has strong anti-spermatogenic activity by decreasing sperm parameters. This study strongly proposes that this plant can be a good candidate for manufacturing antifertility drugs.

Expression patterns of the activator type of cAMP-responsive element modulator in testicular germ cells of Japanese Black bulls

The characterization and quantitative analyses of the key transcription factors for spermiogenesis are necessary in the identification of causal factors for the production of the seemingly normal sperm with dysfunctions in Japanese Black bulls and further elucidation of whole aspect of molecular mechanisms for spermiogenesis in livestock. The objective of this study was to obtain the information regarding the characterization and individual changes of an activator cAMP-responsive element modulator (CREM), which is necessary to the normal progress of spermiogenesis and is required for the transcriptional activity of genes coding essential factors for the sperm fertilization ability in rodents, using testes from 21 Japanese Black bulls with the ability to produce sperm indicating the normal motility and morphology. The bull CREM ταγ (one of activator variants) was detected in testes more strongly than livers by reverse transcription–polymerase chain reaction and Northern blotting. This variant was localized in the nuclei of spermatids as shown by indirect immunofluorescence with the homemade mouse antiserum. The motility and morphology of the cauda epididymal sperm from 16 Japanese Black bulls were examined before the quantitative analyses of testicular activator CREM to confirm the ability to produce sperm with normal motility and morphology in these males. The percentages of the motile sperm, those of the sperm with the normal acrosomes, and those of morphologically normal sperm were 60.0% to 90.0%, 88.0% to 100%, and 83.0% to 97.9%, respectively. The quantitative analyses with real-time polymerase chain reaction using the testicular RNA from the same bulls revealed that the relative expression levels of activator CREM variants in testes varied significantly among these bulls in the range from 0.56 to 1.64 (P < 0.05). These results are consistent with the suggestions that CREM ταγ are involved in the spermiogenesis in the testes of Japanese Black bulls and that the expression levels of the activator CREM variant mRNAs in the testes are varied significantly among individual bulls that have the ability to produce sperm with the normal motility and morphology.

EXPRESSION PROFILING OF CREM GENE IN TESTIS WITH NORMAL AND IMPAIRED SPERMATOGENESIS IN EGYPTIAN MALES

cAMP responsive element modulator (CREM) is one of the most important transcription factors expressed in male testes which connect the extra cellular signals to gene regulation. CREM expression switches from a repressor to an activator in testes during spermatogenesis. Any alteration in this switch leads to different testicular patterns. Methods: Total RNA was extracted from Eighty eight testicular biopsy and analyzed for CREM expression profiling. Normal spermatogenesis showed expression of CREM2and gamma repressor, the same finding was detected in Hypospermatogenesis group but with another longer repressor belong to alpha repressor type, 95% of Round spermatid maturation arrest group showed two repressor patterns, and 5% showed two activator transcripts of CREM2 activator. Sertoli cells only group didn’t show any activator transcripts of CREM. In conclusion studying the mechanisms of interaction between CREM repressors and activators in the normal and impaired spermatogenesis may lead to better understanding of genetic control of the spermatogenesis and consequently to better treatment options.

Epistatic Interactions between CREB and CREM Variants in Affective Disorder.

The aim of the present work is to investigate the existence of epistatic interactions possibly influencing psychotropic agents' response between rs6740584 within Cyclic adenosine monophosphate Response Element Binding (CREB) and rs12775799 within cAMP response element-modulator (CREM) variants in bipolar disorder (BD) and major depressive disorder (MDD). All BD and MDD patients were administered with the Young Mania Rating Scale (YMRS) and Hamilton Depression Rating Scale (HAMD) at baseline and at endpoint, respectively. A multiple regression model was employed to investigate the existence of possible epistatic interactions between the two variants and diverse clinical factors including drug response in affective disorders. No significant epistatic interaction was observed between rs6740584 within CREB and rs12775799 within CREM on both symptom improvement and other clinical factors in affective disorders. Our preliminary results suggest that no epistatic interaction between rs6740584 within CREB and rs12775799 within CREM should exist on clinical improvement and clinical factors in affective disorders.

CAMP Responsive Element Modulator (CREM) α Mediates Chromatin Remodeling of CD8 during the Generation of CD3+CD4−CD8− T Cells

TCR-αβ(+)CD3(+)CD4(-)CD8(-) "double negative" T cells are expanded in the peripheral blood of patients with systemic lupus erythematosus (SLE) and lupus-prone mice. Double negative T cells have been claimed to derive from CD8(+) cells that down-regulate CD8 co-receptors and acquire a distinct effector phenotype that includes the expression of proinflammatory cytokines. This, along with the fact that double negative T cells have been documented in inflamed organs, suggests that they may contribute to disease expression and tissue damage. We recently linked the transcription factor cAMP responsive element modulator (CREM) α, which is expressed at increased levels in T cells from SLE patients and lupus prone MRL/lpr mice, with trans-repression of a region syntenic to the murine CD8b promoter. However, the exact molecular mechanisms that result in a stable silencing of both CD8A and CD8B genes remain elusive. Here, we demonstrate that CREMα orchestrates epigenetic remodeling of the CD8 cluster through the recruitment of DNA methyltransferase (DNMT) 3a and histone methyltransferase G9a. Thus, we propose that CREMα is essential for the expansion of double negative T cells in SLE. CREMα blockade may have therapeutic value in autoimmune disorders with DN T cell expansion.