Human CATSPER1 Promoter Is Regulated by CREB1 and CREMτ Transcriptional Factors In Vitro

Oviedo, Norma; Ortiz-Borrayo, Lizdy; Hernández‐Sánchez, Javier; Jiménez-Badillo, Salma E; Tesoro-Cruz, Emiliano; Moreno-Navor, Esperanza; Aguirre-Alvarado, Charmina; Bekker-Méndez, Carolina

doi:10.1016/j.arcmed.2018.06.004

Cited by 6 publications

(5 citation statements)

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“…CREB1 is a member of the leucine zipper family responsible for DNA binding. In HEK293 and GC1-spg cells, CREB1 could upregulate CATSPER1, which plays critical roles in flagellum hyperactivation of the spermatozoa ( 60 ). Gene deletion of SIN3A in the Sertoli cells was reported to lead to the defect of undifferentiated spermatogonia and the downregulation of stem cell-associated markers in fetal mice ( 61 ).…”

Section: Discussionmentioning

confidence: 99%

Aberrant Gene Expression Profiling in Men With Sertoli Cell-Only Syndrome

et al. 2022

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Sertoli cell-only syndrome (SCOS) is the most severe and common pathological type of non-obstructive azoospermia. The etiology of SCOS remains largely unknown to date despite a handful of studies reported in this area. According to the gene expression of testicular tissue samples in six datasets from the Gene Expression Omnibus, we detected 1441 differentially expressed genes (DEGs) between SCOS and obstructive azoospermia (OA) testicular tissue samples. Enriched GO terms and KEGG pathways for the downregulated genes included various terms and pathways related to cell cycle and reproduction, while the enrichment for the upregulated genes yielded many inflammation-related terms and pathways. In accordance with the protein-protein interaction (PPI) network, all genes in the most critical module belonged to the downregulated DEGs, and we obtained nine hub genes, including CCNB1, AURKA, CCNA2, BIRC5, TYMS, UBE2C, CDC20, TOP2A, and OIP5. Among these hub genes, six were also found in the most significant SCOS-specific module obtained from consensus module analysis. In addition, most of SCOS-specific modules did not have a consensus counterpart. Based on the downregulated genes, transcription factors (TFs) and kinases within the upstream regulatory network were predicted. Then, we compared the difference in infiltrating levels of immune cells between OA and SCOS samples and found a significantly higher degree of infiltration for most immune cells in SCOS than OA samples. Moreover, CD56bright natural killer cell was significantly associated with six hub genes. Enriched hallmark pathways in SCOS had remarkably more upregulated pathways than the downregulated ones. Collectively, we detected DEGs, significant modules, hub genes, upstream TFs and kinases, enriched downstream pathways, and infiltrated immune cells that might be specifically implicated in the pathogenesis of SCOS. These findings provide new insights into the pathogenesis of SCOS and fuel future advances in its theranostics.

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Section: Discussionmentioning

confidence: 99%

Aberrant Gene Expression Profiling in Men With Sertoli Cell-Only Syndrome

et al. 2022

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“…CREMs activates various genes during spermatogenesis, including Catsper1; however, most are expressed in post-meiotic stages [16,[53][54][55][56][57][58][59]. Repressor isoforms of the CREM protein (CREMa, CREMb and CREMc) are expressed in spermatogonia (GC-1 spg) cells [42]; so, deletion of the only CRE site of the minimal promoter results in an increased transcriptional activity.…”

Section: Discussionmentioning

confidence: 99%

“…Even though the relevance of Catsper2 in male fertility is well established, the mechanism by which this gene is transcriptionally regulated is unknown. We previously reported that the cAMP Responsive Element Modulator s isoform (CREMs) regulates the CATSPER1 promoter activity in vitro [16]. CREMs is a testis-specific isoform of the Crem gene that contains a basic region and leucine zipper domains for CRE site recognition and DNA binding, in addition to 3 activation domains (Q1, Q2 and KID) for transcriptional activation [17][18][19].…”

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confidence: 99%

Characterization of the promoter region of the murine Catsper2 gene

et al. 2022

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CATSPER2 (Cation channel sperm‐associated protein 2) protein, which is part of the calcium CATSPER channel located in the membrane of the flagellar principal piece of the sperm cell, is only expressed in the testis during spermatogenesis. Deletions or mutations in the Catsper2 gene are associated with the deafness‐infertility syndrome (DIS) and non‐syndromic male infertility. However, the mechanisms by which Catsper2 is regulated are unknown. Here, we report the characterization of the promoter region of murine Catsper2 and the role of CTCF and CREMτ in its transcription. We report that the promoter region has transcriptional activity in both directions, as determined by observing luciferase activity in mouse Sertoli and GC‐1 spg transfected cells. WGBS data analysis indicated that a CpG island identified in silico is non‐methylated; Chromatin immunoprecipitation (ChIP)‐seq data analysis revealed that histone marks H3K4me3 and H3K36me3 are present in the promoter and body of the Catsper2 gene respectively, indicating that Catsper2 is subject to epigenetic regulation. In addition, the murine Catsper2 core promoter was delimited to a region between −54/+189 relative to the transcription start site (TSS), where three CTCF and one CRE binding site were predicted. The functionality of these sites was determined by mutation of the CTCF sites and deletion of the CRE site. Finally, ChIP assays confirmed that CREMτ and CTCF bind to the Catsper2 minimal promoter region. This study represents the first functional analysis of the murine Catsper2 promoter region and the mechanisms that regulate its expression.

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“…However, the involvement of the CREMτ-TISP40 heterodimer in the differential transactivation of other genes remains unclear. Additionally, CREMτ has been shown to bind to a CRE site in the human cation channel sperm-associated 1 CATSPER1 promoter [ 59 ] in vitro, as well as CREMτ binding to the murine Catsper2 promoter both in vitro and in vivo [ 60 ], leading to their direct transactivation. This is consistent with the observed reduction in their mRNA levels in Crem -KO mice [ 54 ], indicating that Catsper2 and likely CATSPER1 are direct targets of CREMτ.…”

Section: Genes Regulated By Cremmentioning

confidence: 99%

Novel Aspects of cAMP-Response Element Modulator (CREM) Role in Spermatogenesis and Male Fertility

Sánchez‐Jasso

López-Guzmán

Bermúdez‐Cruz

et al. 2023

IJMS

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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. Therefore, CREM expression could be used as a biomarker to detect and even counteract male infertility. This review examines the importance of CREM as a transcription factor for sperm production and its relevance in male fertility, infertility and the response to environmental xenobiotics that may affect CREMτ expression and the downstream regulation that alters male fertility. Also, some health disorders in which CREM expression is altered are discussed.

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Human CATSPER1 Promoter Is Regulated by CREB1 and CREMτ Transcriptional Factors In Vitro

Cited by 6 publications

References 50 publications

Aberrant Gene Expression Profiling in Men With Sertoli Cell-Only Syndrome

Aberrant Gene Expression Profiling in Men With Sertoli Cell-Only Syndrome

Characterization of the promoter region of the murine Catsper2 gene

Novel Aspects of cAMP-Response Element Modulator (CREM) Role in Spermatogenesis and Male Fertility

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