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Sci."],"published-print":{"date-parts":[[2026,2]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Cation channel sperm-associated protein 4 (CATSPER4) is a subunit of the sperm-specific cation\/calcium channel, CatSper, located in the principal piece of the sperm flagellum. It is expressed during the late stages of spermatogenesis, and disruption of the gene encoding this protein leads to male infertility. Mutations in\n                    <jats:italic>Catsper4<\/jats:italic>\n                    are linked to asthenozoospermia. However, the molecular mechanisms regulating\n                    <jats:italic>Catsper4<\/jats:italic>\n                    expression remain unclear. Here, we present a detailed molecular characterization of the\n                    <jats:italic>Catsper4<\/jats:italic>\n                    promoter in mice, focusing on the role of the cAMP-responsive element modulator isoform \u03c4 (CREM\u03c4) in its transcriptional regulation. Analysis of publicly available metagenomic chromatin immunoprecipitation-sequencing (ChIP-seq) data revealed the presence of activation histone marks\u2014H3K4me3, H3K4me1, and H3K27ac\u2014within a region corresponding to the 631\u00a0bp predicted promoter, suggesting an active promoter region. Although the predicted\n                    <jats:italic>Catsper4<\/jats:italic>\n                    promoter showed minimal activity, a 65\u00a0bp deletion at the 3\u2032-end of the promoter significantly enhanced the transcription. Moreover, removal of the 239\u00a0bp in the 5\u2032-flanking region also increased the transcriptional activity, indicating that the core promoter region spans the region from \u2212\u200999 to +\u200963\u00a0bp relative to the transcription start site (TSS). Notably, a cAMP-responsive element was predicted at +\u200991, a relevant site in the regulation of other\n                    <jats:italic>Catsper<\/jats:italic>\n                    family genes. To explore its function, we mutated this site and overexpressed CREM\u03c4. Electrophoretic mobility shift assays (EMSA) and ChIP assays confirmed that CREM\u03c4 binds to the murine\n                    <jats:italic>Catsper4<\/jats:italic>\n                    promoter both in vitro and in vivo. This study provides the first functional analysis of the\n                    <jats:italic>Catsper4<\/jats:italic>\n                    promoter, shedding light on the mechanisms regulating its expression and highlighting the key role of CREM\u03c4 in this process.\n                  <\/jats:p>","DOI":"10.1007\/s43032-025-02029-9","type":"journal-article","created":{"date-parts":[[2026,2,12]],"date-time":"2026-02-12T19:53:56Z","timestamp":1770926036000},"page":"411-423","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Molecular Characterization of the Murine Catsper4 Promoter and its Regulation by CREM\u03c4"],"prefix":"10.1007","volume":"33","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4381-4931","authenticated-orcid":false,"given":"Sergio Federico","family":"L\u00f3pez-Guzm\u00e1n","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-1229-4232","authenticated-orcid":false,"given":"Diego Eduardo","family":"S\u00e1nchez-Jasso","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5773-6877","authenticated-orcid":false,"given":"Javier","family":"Hern\u00e1ndez-S\u00e1nchez","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2359-5751","authenticated-orcid":false,"given":"Norma","family":"Oviedo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0463-9357","authenticated-orcid":false,"given":"Rosa Maria","family":"Bermudez-Cruz","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2026,2,12]]},"reference":[{"key":"2029_CR1","doi-asserted-by":"publisher","first-page":"153","DOI":"10.1038\/ncomms1153","volume":"2","author":"J-J Chung","year":"2011","unstructured":"Chung J-J, Navarro B, Krapivinsky G, Krapivinsky L, Clapham DE. A novel gene required for male fertility and functional CATSPER channel formation in spermatozoa. Nat Commun. 2011;2:153. https:\/\/doi.org\/10.1038\/ncomms1153.","journal-title":"Nat Commun"},{"key":"2029_CR2","doi-asserted-by":"publisher","first-page":"e23082","DOI":"10.7554\/eLife.23082","volume":"6","author":"J-J Chung","year":"2017","unstructured":"Chung J-J, Miki K, Kim D, Shim S-H, Shi HF, Hwang JY, Cai X, Iseri Y, Zhuang X, Clapham DE. CatSper\u03b6 regulates the structural continuity of sperm Ca2\u2009+\u2009signaling domains and is required for normal fertility. eLife. 2017;6:e23082. https:\/\/doi.org\/10.7554\/eLife.23082.","journal-title":"eLife"},{"key":"2029_CR3","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2304409120","volume":"120","author":"X Huang","year":"2023","unstructured":"Huang X, Miyata H, Wang H, Mori G, Iida-Norita R, Ikawa M, et al. A CUG-initiated CATSPER\u03b8 functions in the CatSper channel assembly and serves as a checkpoint for flagellar trafficking. Proc Natl Acad Sci. 2023;120:e2304409120. https:\/\/doi.org\/10.1073\/pnas.2304409120.","journal-title":"Proc Natl Acad Sci"},{"key":"2029_CR4","doi-asserted-by":"publisher","first-page":"746","DOI":"10.1038\/s41586-021-03742-6","volume":"595","author":"S Lin","year":"2021","unstructured":"Lin S, Ke M, Zhang Y, Yan Z, Wu J. Structure of a mammalian sperm cation channel complex. Nature. 2021;595:746\u201350. https:\/\/doi.org\/10.1038\/s41586-021-03742-6.","journal-title":"Nature"},{"key":"2029_CR5","doi-asserted-by":"publisher","first-page":"18945","DOI":"10.1074\/jbc.M701083200","volume":"282","author":"J Liu","year":"2007","unstructured":"Liu J, Xia J, Cho K-H, Clapham DE, Ren D. CatSper\u03b2, a novel transmembrane protein in the CatSper channel complex. 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