cAMP-Response Element Modulator in Spermatogenesis and male fertility.: Comparison
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Spermatogenesis is a very complex process with an intricate transcriptional regulation. The transition from the diploid to the haploid state requires the involvement of specialized genes in meiosis, among other specific functions for the formation of the spermatozoon. The transcription factor cAMP-response element modulator (CREM) is a key modulator that triggers the differentiation of the germ cell into the spermatozoon through the modification of gene expression. CREM has multiple repressor and activator isoforms whose expression is tissue-cell-type specific and tightly regulated by various factors at the transcriptional, post-transcriptional and post-translational level. The activator isoform CREMτ controls the expression of several relevant genes in post-meiotic stages of spermatogenesis. In addition, exposure to xenobiotics negatively affects CREMτ expression, which is linked to male infertility. On the other hand, antioxidants could have a positive effect on CREMτ expression and improve sperm parameters in idiopathically infertile men.

  • CREM
  • spermatogenesis
  • male fertility
  • gene regulation
  • CREM isoforms

1. Introduction

Spermatogenesis is regulated by signals from the hypothalamic–pituitary–gonadal axis. Upon the onset of puberty, this axis triggers the release of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) [1]. LH reaches the Leydig cells in the testes, stimulating testosterone production. Testosterone then binds to androgen receptors on Sertoli cells, Leydig cells and peritubular myoid cells, and initiates signals that stimulate the spermatogonia differentiation pathway, introducing mature sperm [2]. Spermatogenesis is highly sensitive to testosterone released by Leydig cells and retinoic acid (RA) synthesized by Sertoli cells. After that, germ cells are able to synthesize their own RA [3]. During this process, the expression of exclusive germ cell genes involved in several processes like meiosis, DNA condensation and spermiogenesis are regulated by testis specific transcription factors. Also, some transcripts even undergo translation during maturation in epididymis and sperm capacitation[4][5].
The discovery of the cAMP-response element modulator (CREM) as the major transcription factor for murine spermatogenesis is of great importance. It is able to produce more than 30 isoforms—some of them displaying activating functions and an enhanced expression in the testis [6]. The various isoforms of Crem are produced through molecular events such as transcription from alternative promoters, alternative splicing, alternative polyadenylation and the involvement of destabilizing elements at the 3′ end of RNA [7]. Upon the onset of puberty, the pituitary hormone FSH initiates the expression of Cremτ (activator isoform) [8]. This isoform consists of two Q-rich regions, a Kid domain (kinase-inducible), a basic region, an NLS signal for nuclear import and a leucine zipper at its carboxyl end. CREM has the ability to homodimerize (Figure 1) and heterodimerize with other transcription factors via its leucine zipper domain. Crem recognizes palindromic sequences known as CRE sites with a consensus sequence of TGACGTCA and also an only 4-bp-long sequence known as half-CRE sites. These sequences can also be recognized by cAMP-response-element-binding protein (CREB) [9][10].
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Figure 1. Structure of Cremτ homodimer: The predicted quaternary structure of the cAMP-response element modulator CREMτ homodimer is displayed. Domains are highlighted in different colors. The Q1 and Q2 domains have the ability to interact with proteins of the basal transcription machinery as well as other proteins. Within the kinase-inducible Kid domain, several residues (e.g., S117) can undergo phosphorylation by proteins with kinase activity, such as testis-specific serine kinase (TSSK4) and cAMP-dependent protein kinase (PKA), thereby enhancing their activity. The basic domain is responsible for DNA binding and allows for the recognition of CRE sites. The leucine zipper domain facilitates both hetero- and homodimerization. The basic domain and leucine zipper are commonly abbreviated as the bZIP domain. Regions in grey color are not considered as belong to any domain. Structure prediction was performed using AlphaFhold2 with a CREMτ (NP_001104329.1) mouse AA sequence.
In somatic cells, the activation of CREB and CREM proteins involves phosphorylation and their interaction with coactivator proteins such as CREB-binding protein (CBP) and p300 [11]. However, unlike CREB, CREMτ does not require phosphorylation for activation in germ cells. Instead, its activation occurs through another coactivator protein called Activator of CREM in Testis (ACT) to modulate its nuclear transcriptional activity [12]. ACT contains a LIM domain with two zinc fingers likely to facilitate protein–protein binding [13]. Interestingly, a kinesin protein (KIF17b) regulates ACT also present in germ cells. KIF17b is responsible for clearing ACT from the cell nucleus, thereby preventing the activating function of CREMτ [14]
Despite silencing Act, CREM-dependent genes involved in sperm fertility maintenance continue to be expressed, and instead, the affected gene group is primarily associated with a decrease in sperm count and flagellum motility [15].
An intriguing mechanism involves the coordinated process of transcription, KIF17b facilitated cytoplasmic transport and the translation of Crem-dependent gene mRNAs. This mechanism is mediated by a set of RNA-binding proteins that promote the protection and span of the mRNA half-life of CREM-dependent genes in the cytoplasm [16].

2. CREMτ Expression

It is widely accepted that the up regulation of Crem expression during spermatogenesis occurs in response to LH and FSH signaling[8]. These hormones bind to specific receptors on Leydig and Sertoli cells, leading to an increase in cAMP levels and subsequent changes in gene expression. FSH and forskolin induce an elevated expression of Icer (Inducible cAMP Early Repressor) in rat Sertoli cells. When the ICER protein level increases, it undergoes autoregulation, resulting in a decrease in its expression [17]. Repressor isoforms are initially expressed at low levels in early spermatogonia and spermatocytes. The expression of the activating isoform Cremτ in spermatocytes triggers the expression of meiotic genes crucial for gamete differentiation into spermatozoa. The human CREM gene is located on chromosome 10 (86,108 bp) and consists of eight exons, of which seven exons correspond to the coding sequence of the mRNA (2643 bp) encoding the isoform CREMτ (332 amino acids). In contrast, the mouse Crem gene is located on mouse chromosome 18 (74,504 bp) and contains nine exons, producing a 2362 bp mRNA for the 357aa CREMτ isoform. The mouse Crem gene shares an 86.03% identity with the human gene and encodes a CREMτ protein that shares an 86.63% identity with its human counterpart. To date, 54 transcript isoforms of the human CREM gene, independently of a genome build, have been identified that produce mRNAs ranging from 925 bp to 3500 bp. However, only 17 isoforms and proteins are recognized in specific genomic databases. In contrast, the murine Crem gene has 42 transcript isoforms in the annotated genome GRCm39 C57BL/6J with 18 confirmed isoforms ranging from 529 bp to 2931 pb (Figure 2).
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Figure 2. Mouse Crem isoforms. The structure of 18 confirmed isoforms at transcriptional and protein levels is shown. The mouse Crem gene is located on chromosome 18 in the complementary strand where two lncRNAs (NR_073193.1 and Gm6225) are located in the sense and antisense direction, respectively. The Creb gene is shown above for comparison. The CREM domains in the gene structure are highlighted in different colors at the top and the composition of each isoform is shown. For identification, the Ensembl name of each isoform, the length of the gene in nucleotides (nt), the protein length in amino acids (aa) and the corresponding NCBI ID are listed.
The similarity between the Creb and Crem genes lies in several aspects. Firstly, their first exon does not contain a coding sequence (CDS), and the start translation codon is located in the second exon. In addition, both proteins possess two glutamine-rich activation domains and a P-box site for phosphorylation by PKA, encoded by two exons. The carboxyl terminus of both proteins contains a basic region containing the leucine zipper domain (bZIP) (Figure 2), which allows for DNA binding and homodimerization as well as heterodimerization [7]. The phosphorylation of serine-117 of CREMτ by testis-specific kinase activity in vitro, dependent on changes in cAMP and not the Ca2-calmodulin pathway, has been suggested as a potential regulatory mechanism for the protein [18]. However, it has been demonstrated that the activation of CREMτ during spermatogenesis does not depend on phosphorylation but rather on the presence of Act, which serves as a biological marker for male fertility [12]. Before the expression of the Cremτ isoform in testes, various dominant-negative proteins of CREB, such as CREBγ and CREBα-γ isoforms, are expressed. These isoforms lack the ability to bind to DNA or transactivate genes, but they modulate other CREB isoforms. Low levels of the CREB isoforms δ and α (transactivators) are expressed in primary spermatocytes [19]. The Crem gene encodes different isoforms, including both repressor and activator isoforms. Among the repressors are CREM α, β, γ, CREM-S and ICER, while the isoforms CREMτ 1 and 2 are identified as activating transcription factors essential for spermatogenesis [18]. The CREMΔC-G isoform, which lacks the two glutamine-rich activation domains and the P-box, acts as a repressor and competitor for CRE sites in elongated spermatids (Figure 2) [20]. Both human and murine genes share their promoter region with divergent genes (Cullin 2 (CUL2) and Gm6225), and they exhibit a similar expression profile in different tissues, suggesting the presence of a bidirectional promoter within the Crem promoter region and its first intron. Additionally, there are two enhancers downstream of the CREM gene. One enhancer is associated with NANOG and is marked by modified histone H3K27ac, while the other is labeled with modified histone H3K4me1 [21][22]. Single-cell RNA sequencing data confirm that Cremτ expression in mouse spermatocytes begins depending on the pachytene spermatocytes and reaches its peak expression in stage-VII-to-VIII round spermatids but is absent in elongated spermatids [23]. A similar expression profile of human CREMτ has been observed in normozoospermic males, while oligozoospermic males only maintain the expression of repressor isoforms[24]. However, it should be noted that the expression and localization of CREMτ orthologs might differ in other species; in porcine spermatids and spermatozoa, CREMτ is still detected around the cell nucleus and in the connecting piece, respectively [25]. The expression of CREMτ and its coactivator ACT has been confirmed in human testicular biopsies from patients with obstructive azoospermia (OA), as has its correlation with the expression of transition proteins 1 and 2 (TNP1, 2) and protamines 1 and 2 (PRM1, 2), which are required for the packaging of DNA [26]. Instead, in patients with Sertolli-Cell-Only Syndrome (SCOS), all of these genes are down-regulated, but even in the absence of CREM, a low expression of TNP2 is still seen. Infertile patients diagnosed with arrested round spermatid maturation (SMA) have a low expression of CREMτ and ACT, which negatively correlates with the expression of these genes[26]. These findings are consistent with previous reports on mice and indicate that a reduced expression of Crem and its cofactor Act is associated with post-meiotic arrest and male infertility. The detection of human CREMτ in different tissues shows that its main expression occurs in the testis. It is also expressed in other tissues such as the adrenal gland, placenta, appendix and bladder, reaching levels greater than or approximately 100 transcripts per million [27]in contrast to mouse tissues, which, with the exception of the testis, have a low expression. In patients with obstructive azoospermia, the expression of CREMτ and ACT correlates with the expression of genes involved in chromatin compaction (TPN, PRM1 and PRM2). Infertile patients with post-meiotic arrest and the persistence of round spermatids exhibit a low expression of CREMτ and ACT, which negatively correlates with the expression of these genes. These findings are consistent with previous reports on mice and indicate that a reduced expression of Crem and its cofactor Act is associated with post-meiotic arrest and male infertility [26]. When examining the expression of CREM in different cancers, over-expression has been observed in skin and immune cancers, whereas down-regulation is observed in other types of cancers. However, the detection of CREM protein, which has a well-conserved DNA binding domain among the 28 isoforms recognized, is ambiguous, as the detection may correspond to both repressor and activator isoforms, affecting the interpretation of CREM expression in different tissues[27].

3. CREM Regulation

CREM is widely recognized as a crucial regulator of spermatogenesis; therefore, the comprehension of its modulation at all levels is relevant. A well-established aspect is the direct regulation of CREM activity by ACT-KIFL7b, while the involvement of other ACT-like factors is still largely unclear (see [16] for the latest review). This section focuses on analyzing recent reports on new CREM modulators at transcriptional, post-transcriptional and post-translational levels and their mechanisms, which are summarized in Figure 3.
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Figure 3. Mechanisms of Crem regulation. Transcriptional regulation of Crem (left panel): Hypermethylation of the Crem promoter leads to a reduction in CREM expression, resulting in the decreased expression of protamine genes and, consequently, an abnormal protamination is produced. Death-Associated Protein-like 1 (DAPL1) is able to reduce the expression of Crem transcripts through an unknown mechanism. Post-transcriptional regulation of Crem (middle panel): Sertoli cells recognize Follicle-stimulating hormone (FSH), and through an unknown mechanism, induce the stabilization of Cremτ mRNA in germ cells. Deleted in azoospermia-associated protein 1 (DAZAP1) and stimulatory cleavage factor (τCSTF-64) can bind to newly synthesized mRNA in Crem intron 3, mediating the inclusion and exclusion of Crem exon 4 (Q1 domain), respectively. Regulation of CREM protein activity (right panel): H3K9me1/H3K9me2 lysine demethylase JMJD1a, τCSTF-64 and Tudor domain protein 5 (TDRD5) indirectly modulate the activity of CREM protein, either enhancing or maintaining the expression of its coactivator ACT. JMJD1a also maintains low methylation levels on promoters of the Crem target gene, facilitating the correct positioning of CREM. TSSK4 interacts with CREM and phosphorylates its S117, increasing CREM activity. Protein arginine methyltransferase (CARM1) methylates p300, preventing it from interacting with ACT and reducing CREMτ transactivation. Sperm-associated antigen 8 (SPAG8) interacts with ACT, aiding in the binding of ACT with CREMτ, but without forming a SPAG8-ACT-CREMτ complex, thereby increasing the transcriptional activity of CREMτ. GCNF interacts and competes with CREMτ for binding to CRE/NR sites, suppressing its activity. Lastly, kinesin protein (KIF17b) “kidnaps” ACT, taking it to the cytoplasm and preventing ACT-CREMτ interaction.

4. Genes Regulated by CREM

The critical role of CREMτ in spermatogenesis has been highlighted since the generation of Cremτ-deficient mice. These mice exhibit a decreased expression of testis-specific genes, including Prm1, Prm2, Tnp1, Tnp2, sperm-mitochondria-associated cysteine-rich protein (Mcs), Rt7, high-affinity Ca2+/calmodulin-binding protein Calspermin (Camk4) and early growth response Egr2 (Krox-20) and Egr1 (Krox-24), being the first reported set of genes regulated by CREM[28][29]. Over time, a growing number of genes have been proposed as potential targets of CREMτ regulation.

5. Male Fertility and CREM

Two research groups in 1996, one led by Sassone-Corsi and the other by Günther Schütz, concurrently described the first mouse model lacking Crem; both studies provided compelling evidence for the impact of a CREM deficiency on spermatogenesis, including the loss of the expression of vital genes for spermatogenesis, arrest at the initiation of spermiogenesis and the absence of sperm production[28][29]. The transcription factor CREM plays a central role in the formation of male haploid cells, as it is responsible for activating genes Involved in meiotic machinery and spermatogenic cell morphogenesis. In a mouse obesity model, a decrease in Crem, adaptor protein 1 (Sh2b1), desert hedgehog (Dhh), insulin-like growth factor 1 (Igf1) and leptin receptor (Lepr) transcript levels was observed, resulting in impaired fertility, such as a reduced sperm motility and decreased mating rates of obese males with female mice [30]. Consequently, it is plausible that CREM homologs may play a similar fundamental role in fertility in other species. Male fertility also relies on the presence of several CREM cofactors, including ACT, KIF17b and SPAG48, which are crucial for the successful development of spermatogenic cells [12][31][32]. Studies in infertile populations have revealed the absence or low expression of CREM or its cofactors, contributing to infertility. In the case of the CREM cofactor ACT, studies in infertile patients with azoospermia or oligozoospermia have identified specific single nucleotide polymorphisms (SNPs) resulting in amino acid changes in the ACT coding region, that, combined to the haplotype 204G-211V-243R-12065G, reduce the interaction between ACT and CREM by 45%, as observed in an in vitro double hybrid test [33]. Similarly, various SNPs found in CREM and its cofactors have been linked to non-obstructive azoospermia (NOA) in patients. SNP rs4934540 in an intron region with a TT or CT genotype confers susceptibility to NOA, while a CT or CC genotype in SNP rs4934540 and an AG genotype of rs2295415 (at the 3′ untranslated end of CREM) reduce the NOA risk. The combination of four CREM SNPs in different haplotypes provides either protection (CGTG) or a high risk (TATG) for spermatogenic failure, as confirmed with expression assays, which showed a low CREM expression[34]. Patients with Klinefelter syndrome commonly experience hypogonadism, low testosterone levels and fertility problems. Testicular biopsies from these patients with mature sperm have demonstrated a lower expression of genes such as CREM and CSF-1, as well as an absence or reduced expression of protamine compared to azoospermic patients without Klinefelter syndrome but in whom complete spermatogenesis was observed histologically [35]. Most Klinefelter patients with SCO show no CREM and protamine expression with CSF-1 expression; however, CREM and protamine levels are still detectable in some patients[35]. Furthermore, alterations in the expression of activating isoforms of CREMτ, namely CREMτ1 and CREMτ2 from the P3 and P4 promoters, respectively, have been observed in patients with spermatogenesis arrest and testicular tumors [36]. Likewise, the involvement of CREM and ACT in the occupation of CRE sites in the promoters of the target genes TNP1 and 2, as well as PRM 1 and 2, in patients with the arrest of round spermatid maturation (SMA) compared to obstructive azoospermia (OA) as a positive control was evaluated. Both CREM and ACT are down-regulated in the group of SMA patients, and low levels of expression in the target genes TNP 1 and 2 and PRM 1 and 2 were also found. A low occupancy of CREM and ACT was also observed in the promoter regions of the TNP1 and 2 and PRM1 and 2 genes in the SMA group, but it could be a result of the low CREM and ACT expression [26]. This confirms CREM’s role as a transcription factor in the development of human spermatogenesis and fertility. Moreover, the CREM promoter contains two CpG islands with a total of 73 CpG sites, making it susceptible to methylation. Differentially methylated sites in CREM have been associated with an impaired sperm DNA integrity in infertile patients [37]. However, bisulfite sequencing studies did not find significant differences in CREM promoter methylation in patients with oligozoospermia or abnormal protamination levels, except for two infertile patients who exhibited a distinct pattern of high methylation[38]. In contrast, a separate pyrosequencing study revealed high levels of DNA methylation in the CREM promoter in patients with oligozoospermia and abnormal protamination, with a negative correlation to the sperm count, morphology and motility[38]. Infection with Toxoplasma gondii has been shown to decrease the reproductive capacity of mice, leading to a noticeable decline in sperm production. An analysis of global methylation in the testicular tissue of infected animals revealed slight differences in methylation levels at specific sites in the Crem promoter [39]. These methylation-prone sites in the CREM promoter can modulate its expression in response to environmental or genotoxic factors, emphasizing their significance as critical determinants of sperm fertility.

6. Impact of Xenobiotics in CREMτ Regulation

Previously, the transcriptional regulation of Cremτ was discussed. However, diverse studies suggest that CREMτ is also subject to regulation by xenobiotics. Even though these foreign molecules seem to exert both positive and negative effects on fertility [40][41] extensive research needs to be performed to corroborate if the effect shown in CREMτ levels is due to a lack of a cell population expressing CREM or the direct regulation of the CREM transcript or protein.

6.1. CREM Disruption by ROS Production Xenobiotics

In recent years, there has been increasing evidence linking environmental pollutants to semen quality and spermatogenesis impairment, leading to a rise in male infertility rates [42][43]. Several studies have suggested that this effect is due to a down-regulation of CREM pollutants such as solvents, fluoride, pesticides and silica nanoparticles (SiNPs) that seem to be negative regulators of CREM expression[43][44][45]. Common pollutants like 1,2-dichloroethane (1,2-DCE), a widely used solvent, and fluoride, a prevalent contaminant in industrialized countries’ drinking water, seem to reduce CREM expression and its coactivator ACT in a dose-dependent manner. Interestingly, both pollutants are also associated with a decreased semen quality, including increased sperm malformation and a reduced concentration, viability and motility[44][45] Additionally, 1,2-DCE exposures have been linked to the vacuolar degeneration of germ cells, sloughing of spermatogenic cells and increased apoptosis in the testes, resembling the phenotype observed in CREM-knockout mice[28][29]. The pesticide carbendazim (CBZ), another commonly used chemical, has been found to down-regulate CREM expression and decrease sperm concentration and motility. Notably, CBZ disrupts epigenetic markers such as H3K27, 5mC and 5hmC, suggesting that certain pollutants may alter the epigenetic regulation of genes involved in spermatogenesis [45]. Similarly, silica nanoparticles have been shown to reduce sperm quantity and quality by impairing the epigenetic regulation of spermatogenesis and inducing the hypermethylation of the CREM promoter, resulting in CREM down-regulation[38]. It is worth noting that not only pollutants but also certain medical treatments can negatively impact CREM expression. Cistanches herba (CH), a tonic commonly used in Eastern societies, has been found to down-regulate CREM expression in a dose-dependent manner while reducing the testosterone levels, sperm count and sperm motility, mirroring the phenotype observed in pollutant-induced CREM down-regulation [46]. Furthermore, radiation therapy, a known treatment with detrimental effects on the male reproductive system, including permanent infertility, has been shown to decrease CREM expression, decrease testis weight and induce atrophic seminiferous tubules [47]. The down-regulation of CREM by various compounds, whether pollutants or medical treatments, can impair spermatogenesis and lead to male infertility. These xenobiotics likely exert their effects through the production of high levels of reactive oxygen species (ROS), which are associated with testicular damage and male infertility (reviewed in [48]) (Figure 4A). Nevertheless, further research needs to be performed to unravel if the deregulation of CREM by these xenobiotics is because of a down-regulation of Crem per se or due to a lowering of cell populations expressing Crem.
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Figure 4. Effect of xenobiotics on Crem regulation. (A) Xenobiotics that produce ROS down-regulate CREM/ACT expression and damage DNA and protein. This affects sperm quality and reduces sperm concentration and motility. (B) Antioxidants quench ROS, enhancing Crem expression. This is associated with better semen quality parameters such as sperm concentration and motility.

6.2. CREM Up-Regulation by Antioxidants

The up-regulation of CREMτ has been associated with improved semen quality parameters, including sperm concentration and motility [36][30][33]. Traditional Eastern herbal remedies are promising since they have shown a positive impact on CREMτ expression. For example, Rubi Fructus (RF), derived from the dried fruit of Rubus coreanus; Yukmijihwang-tang (YJT), a multiherbal formula used to address male reproductive issues; and MYOMI, a Korean herbal medicine, have traditionally been used to enhance male fertility [49],[50],[51]. Studies administering these formulations to mice have demonstrated an increased sperm concentration and motility, accompanied by an enhancement in Cremτ mRNA and protein levels [51][52]. RF constituents are known for their antioxidant properties[48][52][53][54], while YJT and MYOMI, when tested in combination with cyclophosphamide, a commonly used chemotherapy drug, exhibited a reduced lipid peroxidation, indicating an antioxidant effect [55][56]. Antioxidant supplementation has been found to have a protective effect on male fertility [57] For instance, lutein administration following testicular torsion reduced morphological damage to seminiferous tubules and alleviated testicular oxidative stress. Furthermore, Cremτ expression was restored in lutein-treated mice subjected to testicular torsion[58]. Another essential antioxidant, folic acid, a B-complex vitamin, enhanced semen quality in older roosters. Aging is known to be a factor contributing to male infertility, and folic acid supplementation increased semen volume, sperm concentration and sperm motility in older roosters. Additionally, it led to enhanced mRNA levels of important genes involved in spermatogenesis, including Cremτ [59]. Moreover, antioxidant supplementation in patients with idiopathic infertility resulted in the activation of proteins related to the CREM signaling pathway, such as protein kinase cAMP-dependent regulatory subunits (PRKAR1A, PRKAR2A and PRKACA) and lactate dehydrogenase C (LDHC) [60] Taken together, these studies suggest an improvement in semen parameters and Crem levels due to the ability of antioxidants to quench ROS produced by different types of stress (Figure 4B)

7. Other CREM Implications in Health and Disease

As previously mentioned, Cremτ serves as a crucial regulator of spermatogenesis, but it also plays a role in various other molecular mechanisms. Several Crem isoforms have been identified, each with distinct functions beyond spermatogenesis. Repressive isoforms of Crem are involved in the regulation of genes associated with brain function, β cells and immune responses. One such isoform, ICER, participates in numerous neurological processes, including long-term memory, neuronal plasticity, apoptosis and epileptogenesis [61][62][63]. Notably, ICER interacts with brain-derived neurotrophic factor (BDNF) and the signal transducer activator of transcription (STAT3) to bind to pCREB in the Gaba α1 promoter, thereby repressing its transcription in cortical neurons[64][65]. Additionally, ICER modulates adipokine production by inhibiting Creb and suppressing negative effectors of adiponectin, facilitated glucose transporter 4 (GLUT4) and activating transcription factor 3 (ATF3) in adipocytes [66][67]. Another metabolic pathway regulated by ICER is insulin production and secretion. ICER binds to the promoters of genes involved in the insulin pathway, and an increased ICER expression induced by oxidized LDL inhibits insulin production and secretion [68][69]. Furthermore, ICER plays a role in mediating the circadian rhythm in the liver by repressing the period circadian regulator (Per1) gene promoter [70]. It is also implicated in vascular smooth muscle cell apoptosis and proliferation[71]. Another repressive isoform, CREMα, is primarily involved in regulating genes related to the immune system. CREMα acts as a negative regulator of the Cd68 gene promoter and the interleukin Il-2 gene. Surprisingly, it increases the expression of Il17a through epigenetic remodeling [72][73]. CREMα is implicated in immune disorders such as Systemic Lupus Erythematosus (SLE), where its expression is enhanced by transcription factor SP1 and histone lysine methyltransferase SET1 binding to the Crem P1 promoter. This results in increased H3K4me3, decreased DNA methyltransferase 3a (DNMT3a) and the subsequent CREM methylation promoter, leading to the over-expression of CREMα [73][74]. CREMα also binds to the Il17f promoter and represses its expression [75], contributing to accelerated inflammation and autoimmunity [75][76]. In summary, CREM isoforms play diverse roles in various signaling pathways associated with health and disease. However, further extensive research is necessary to fully understand the involvement of other CREM isoforms in different signaling pathways.

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