# CREM

## Overview
The CREM gene encodes the cAMP responsive element modulator, a transcription factor that plays a pivotal role in the regulation of gene expression in response to cAMP signaling pathways. As a member of the CREB/ATF family, the CREM protein is characterized by its basic leucine zipper (bZIP) domain, which facilitates DNA binding and dimerization, allowing it to interact with cAMP response elements (CREs) (Walker1994An; Foulkes1991CREM). The gene undergoes extensive alternative splicing, producing multiple isoforms that can function as transcriptional activators or repressors, depending on the cellular context (Gellersen1997Human). CREM is particularly significant in the hypothalamic-pituitary-gonadal axis, where it is essential for spermatogenesis, and in the pineal gland, where it regulates circadian rhythms by influencing melatonin synthesis (SassoneCorsi1998Coupling). The protein's activity is modulated by post-translational modifications and interactions with other proteins, such as CREB and FHL proteins, which can alter its transcriptional activity (Fimia2000A; De1999Signaling). Alterations in CREM expression and function have been implicated in various diseases, including cardiac arrhythmias, inflammatory bowel disease, systemic lupus erythematosus, and Type 1 Diabetes (Schulte2016Cardiac; Zouidi2017CREM; Wojcik2018GenomeWide; Rauen2011A).

## Structure
The CREM (cAMP responsive element modulator) protein is characterized by a complex molecular structure that includes several functional domains. It contains a basic leucine zipper (bZIP) domain, which is crucial for DNA binding and dimerization, allowing it to interact with cAMP response elements (CREs) (Walker1994An; Foulkes1991CREM). The protein also features a leucine zipper motif and a basic domain, which are essential for its DNA-binding capabilities (Foulkes1991CREM).

CREM undergoes extensive alternative splicing, resulting in multiple isoforms with distinct functions. These isoforms include transcriptional activators and repressors, some of which lack transactivation domains (Gellersen1997Human). For instance, the CREMτ isoform is significant in spermatogenesis and includes Q-rich regions, a kinase-inducible domain (Kid), and a nuclear localization signal (SánchezJasso2023Novel). The CREMAC-G isoform, expressed during spermatogenesis, lacks the phosphorylation domain and acts as a repressor of cAMP-induced transcription (Walker1994An).

Post-translational modifications, such as phosphorylation, play a role in modulating CREM's activity. The presence of putative phosphorylation sites for protein kinases suggests potential regulatory mechanisms (Foulkes1991CREM). These modifications can influence the protein's function and its interaction with other transcription factors.

## Function
The CREM (cAMP responsive element modulator) gene plays a significant role in regulating gene expression in response to cAMP signaling pathways. It is part of the CREB/ATF family of transcription factors and can function as both an activator and a repressor of transcription, depending on the isoform and cellular context. CREM is involved in the nuclear response to physiological and neuroendocrine stimuli, particularly in the hypothalamic-pituitary-gonadal axis, where it is crucial for spermiogenesis. In postmeiotic cells, CREM is highly expressed and its absence leads to halted spermatogenesis and increased apoptosis in germ cells, a condition that mirrors certain human infertility cases (SassoneCorsi1998Coupling).

CREM's activity is modulated through alternative splicing, which generates various isoforms with distinct functions. These isoforms can bind to cAMP response elements (CREs) in DNA, influencing the transcription of target genes. CREM proteins can form homodimers or heterodimers with CREB, affecting their transcriptional activity. The gene's expression is tissue- and development-specific, allowing it to fine-tune cellular responses to external signals (Foulkes1991CREM; Laoide1993The).

In the pineal gland, CREM regulates circadian rhythms by controlling the expression of serotonin N-acetyltransferase, a key enzyme in melatonin synthesis, thus influencing melatonin production (SassoneCorsi1998Coupling).

## Clinical Significance
Mutations and alterations in the expression of the CREM gene have been implicated in several diseases. In cardiac health, the CREM repressor isoform CREM-IbΔC-X is associated with arrhythmogenic remodeling in ventricular cardiomyocytes, contributing to cardiac arrhythmias and heart failure. Chronic beta-adrenergic stimulation, a factor in heart failure progression, induces CREM repressor isoforms, which may form an arrhythmogenic substrate in chronic heart disease (Schulte2016Cardiac).

In the context of inflammatory bowel disease (IBD) and infections, genetic variants in the CREM gene are linked to susceptibility to Entamoeba histolytica infection, which causes diarrhea. A genome-wide association study identified a significant association between a SNP in the CREM/CUL2 locus and increased risk of E. histolytica-associated diarrhea, suggesting a shared pathway with IBD, Crohn's disease, and ulcerative colitis (Wojcik2018GenomeWide).

CREM is also involved in systemic lupus erythematosus (SLE), where altered CREM expression in T cells is linked to decreased IL-2 production, a characteristic defect in SLE. This alteration is associated with increased infection rates in SLE patients and is regulated by a novel intronic promoter influenced by activator protein-1 (AP-1) (Rauen2011A).

In Type 1 Diabetes (T1D), the CREM gene variant rs17583959 has been associated with increased susceptibility, highlighting its potential role in the disease's genetic predisposition (Zouidi2017CREM).

## Interactions
CREM (cAMP response element modulator) is involved in various protein-protein interactions that influence its role as a transcription factor. CREM interacts with a family of LIM-only proteins known as FHL (four-and-a-half-LIM-domain) proteins, which include ACT (activator of CREM in testis). These interactions are crucial for the transcriptional activation of CREM and CREB (cAMP response element-binding protein) and occur independently of the classical coactivator CBP (CREB-binding protein) and phosphorylation (Fimia2000A). In male germ cells, CREM interacts with ACT, a testis-specific coactivator that bypasses the need for CREM phosphorylation and CBP interaction, converting CREM into a potent transcriptional activator (Fimia1999CBPindependent; De1999Signaling).

CREM also forms heterodimers with CREB, which can modulate transcriptional activity. These heterodimers can either activate or inhibit gene expression depending on the context, with CREM potentially acting as a dominant negative regulator by reducing the activation of cAMP-induced transcription (Foulkes1991CREM; Laoide1993The). Additionally, CREM interacts with the general transcription factor TFIIA, specifically the TFIIAα subunit, in a manner that is independent of phosphorylation, suggesting a role in testis-specific transcription regulation (De2003Transcriptional).


## References


[1. (Fimia1999CBPindependent) Gian Maria Fimia, Dario De Cesare, and Paolo Sassone-Corsi. Cbp-independent activation of crem and creb by the lim-only protein act. Nature, 398(6723):165–169, March 1999. URL: http://dx.doi.org/10.1038/18237, doi:10.1038/18237. This article has 184 citations and is from a highest quality peer-reviewed journal.](https://doi.org/10.1038/18237)

[2. (Schulte2016Cardiac) J. S. Schulte, E. Fehrmann, M. A. Tekook, D. Kranick, B. Fels, N. Li, X. H. T. Wehrens, A. Heinick, M. D. Seidl, W. Schmitz, and F. U. Müller. Cardiac expression of the crem repressor isoform crem-ibδc-x in mice leads to arrhythmogenic alterations in ventricular cardiomyocytes. Basic Research in Cardiology, January 2016. URL: http://dx.doi.org/10.1007/s00395-016-0532-y, doi:10.1007/s00395-016-0532-y. This article has 23 citations and is from a domain leading peer-reviewed journal.](https://doi.org/10.1007/s00395-016-0532-y)

[3. (De2003Transcriptional) Dario De Cesare, Gian Maria Fimia, Stefano Brancorsini, Martti Parvinen, and Paolo Sassone-Corsi. Transcriptional control in male germ cells: general factor tfiia participates in crem-dependent gene activation. Molecular Endocrinology, 17(12):2554–2565, December 2003. URL: http://dx.doi.org/10.1210/me.2003-0280, doi:10.1210/me.2003-0280. This article has 30 citations.](https://doi.org/10.1210/me.2003-0280)

[4. (SánchezJasso2023Novel) Diego Eduardo Sánchez-Jasso, Sergio Federico López-Guzmán, Rosa Maria Bermúdez-Cruz, and Norma Oviedo. Novel aspects of camp-response element modulator (crem) role in spermatogenesis and male fertility. International Journal of Molecular Sciences, 24(16):12558, August 2023. URL: http://dx.doi.org/10.3390/ijms241612558, doi:10.3390/ijms241612558. This article has 3 citations and is from a peer-reviewed journal.](https://doi.org/10.3390/ijms241612558)

[5. (Rauen2011A) Thomas Rauen, Konrad Benedyk, Yuang-Taung Juang, Claus Kerkhoff, Vasileios C. Kyttaris, Johannes Roth, George C. Tsokos, and Klaus Tenbrock. A novel intronic camp response element modulator (crem) promoter is regulated by activator protein-1 (ap-1) and accounts for altered activation-induced crem expression in t cells from patients with systemic lupus erythematosus. Journal of Biological Chemistry, 286(37):32366–32372, September 2011. URL: http://dx.doi.org/10.1074/jbc.M111.245811, doi:10.1074/jbc.m111.245811. This article has 33 citations and is from a domain leading peer-reviewed journal.](https://doi.org/10.1074/jbc.M111.245811)

[6. (Laoide1993The) B.M. Laoide, N.S. Foulkes, F. Schlotter, and P. Sassone-Corsi. The functional versatility of crem is determined by its modular structure. The EMBO Journal, 12(3):1179–1191, March 1993. URL: http://dx.doi.org/10.1002/j.1460-2075.1993.tb05759.x, doi:10.1002/j.1460-2075.1993.tb05759.x. This article has 166 citations.](https://doi.org/10.1002/j.1460-2075.1993.tb05759.x)

[7. (Fimia2000A) Gian Maria Fimia, Dario De Cesare, and Paolo Sassone-Corsi. A family of lim-only transcriptional coactivators: tissue-specific expression and selective activation of creb and crem. Molecular and Cellular Biology, 20(22):8613–8622, November 2000. URL: http://dx.doi.org/10.1128/MCB.20.22.8613-8622.2000, doi:10.1128/mcb.20.22.8613-8622.2000. This article has 263 citations and is from a domain leading peer-reviewed journal.](https://doi.org/10.1128/MCB.20.22.8613-8622.2000)

[8. (SassoneCorsi1998Coupling) Paolo Sassone-Corsi. Coupling gene expression to camp signalling: role of creb and crem. The International Journal of Biochemistry & Cell Biology, 30(1):27–38, March 1998. URL: http://dx.doi.org/10.1016/s1357-2725(97)00093-9, doi:10.1016/s1357-2725(97)00093-9. This article has 188 citations.](https://doi.org/10.1016/s1357-2725(97)00093-9)

[9. (Zouidi2017CREM) Ferjani Zouidi, D. Bouzid, H. Fourati, R. Fakhfakh, T. Kammoun, M. Hachicha, C. Penha-Gonçalves, and H. Masmoudi. Crem variant rs17583959 conferred susceptibility to t1d risk in the tunisian families. Immunology Letters, 181:1–5, January 2017. URL: http://dx.doi.org/10.1016/j.imlet.2016.11.007, doi:10.1016/j.imlet.2016.11.007. This article has 3 citations and is from a peer-reviewed journal.](https://doi.org/10.1016/j.imlet.2016.11.007)

[10. (Gellersen1997Human) Birgit Gellersen, Rita Kempf, and Ralph Telgmann. Human endometrial stromal cells express novel isoforms of the transcriptional modulator crem and up-regulate icer in the course of decidualization. Molecular Endocrinology, 11(1):97–113, January 1997. URL: http://dx.doi.org/10.1210/MEND.11.1.9875, doi:10.1210/mend.11.1.9875. This article has 84 citations.](https://doi.org/10.1210/MEND.11.1.9875)

[11. (Wojcik2018GenomeWide) Genevieve L. Wojcik, Chelsea Marie, Mayuresh M. Abhyankar, Nobuya Yoshida, Koji Watanabe, Alexander J. Mentzer, Tommy Carstensen, Josyf Mychaleckyj, Beth D. Kirkpatrick, Stephen S. Rich, Patrick Concannon, Rashidul Haque, George C. Tsokos, William A. Petri, and Priya Duggal. Genome-wide association study reveals genetic link between diarrhea-associated entamoeba histolytica infection and inflammatory bowel disease. mBio, November 2018. URL: http://dx.doi.org/10.1128/mbio.01668-18, doi:10.1128/mbio.01668-18. This article has 23 citations and is from a domain leading peer-reviewed journal.](https://doi.org/10.1128/mbio.01668-18)

[12. (De1999Signaling) Dario De Cesare, Gian Maria Fimia, and Paolo Sassone-Corsi. Signaling routes to crem and creb: plasticity in transcriptional activation. Trends in Biochemical Sciences, 24(7):281–285, July 1999. URL: http://dx.doi.org/10.1016/s0968-0004(99)01414-0, doi:10.1016/s0968-0004(99)01414-0. This article has 243 citations and is from a domain leading peer-reviewed journal.](https://doi.org/10.1016/s0968-0004(99)01414-0)

[13. (Walker1994An) W H Walker, B M Sanborn, and J F Habener. An isoform of transcription factor crem expressed during spermatogenesis lacks the phosphorylation domain and represses camp-induced transcription. Proceedings of the National Academy of Sciences, 91(26):12423–12427, December 1994. URL: http://dx.doi.org/10.1073/pnas.91.26.12423, doi:10.1073/pnas.91.26.12423. This article has 61 citations.](https://doi.org/10.1073/pnas.91.26.12423)

[14. (Foulkes1991CREM) Nicholas S. Foulkes, Emiliana Borrelli, and Paolo Sassone-Corsi. Crem gene: use of alternative dna-binding domains generates multiple antagonists of camp-induced transcription. Cell, 64(4):739–749, February 1991. URL: http://dx.doi.org/10.1016/0092-8674(91)90503-q, doi:10.1016/0092-8674(91)90503-q. This article has 474 citations and is from a highest quality peer-reviewed journal.](https://doi.org/10.1016/0092-8674(91)90503-q)