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Despite the wealth of studies describing transcriptome changes upon lncRNA knockdown, there is limited information describing lncRNA-mediated effects on regulatory elements (REs) modulating gene expression. In this study, we investigated how the metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) lncRNA regulates primary target genes using time-resolved MALAT1 knockdown followed by parallel RNA-seq and ATAC-seq assays. The results revealed that MALAT1 primarily regulates specific protein-coding genes and a substantial decrease in the accessibility downstream of the NR4A1 gene that was associated with a decreased NR4A1 expression. Moreover, the presence of an NR4A1-downstream RE was demonstrated by CRISPR-i assays to define a functional MALAT1\/NR4A1 axis. By analyzing TCGA data, we identified a positive correlation between NR4A1 expression and NR4A1-downstream RE accessibility in breast cancer but not in pancreatic cancer. Accordingly, this regulatory mechanism was experimentally validated in breast cancer cells (MCF7) but not in pancreatic duct epithelial carcinoma (PANC1) cells. Therefore, our results demonstrated that MALAT1 is involved in a molecular mechanism that fine-tunes NR4A1 expression by modulating the accessibility of a downstream RE in a cell type-specific manner.<\/jats:p>","DOI":"10.3390\/ijms25105515","type":"journal-article","created":{"date-parts":[[2024,5,20]],"date-time":"2024-05-20T08:20:31Z","timestamp":1716193231000},"page":"5515","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["The Long Non-Coding RNA MALAT1 Modulates NR4A1 Expression through a Downstream Regulatory Element in Specific Cancer Cell Types"],"prefix":"10.3390","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4377-7982","authenticated-orcid":false,"given":"Sara","family":"Wernig-Zorc","sequence":"first","affiliation":[{"name":"Regensburg Center for Biochemistry [RCB], Universit\u00e4t Regensburg, 93053 Regensburg, Germany"},{"name":"St. Anna Children\u2019s Cancer Research Institute, 1090 Vienna, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Uwe","family":"Schwartz","sequence":"additional","affiliation":[{"name":"NGS Analysis Center, Biology and Pre-Clinical Medicine, Universit\u00e4t Regensburg, 93053 Regensburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1718-3387","authenticated-orcid":false,"given":"Paulina","family":"Mart\u00ednez-Rodr\u00edguez","sequence":"additional","affiliation":[{"name":"Programa de Doctorado en Ciencias, menci\u00f3n Biolog\u00eda Celular y Molecular Aplicada, Universidad de La Frontera, Temuco 4811230, Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Josefa","family":"Inalef","sequence":"additional","affiliation":[{"name":"Institute of Anatomy, Histology, and Pathology, Faculty of Medicine, Universidad Austral de Chile, 5090000 Valdivia, Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francisca","family":"Pavicic","sequence":"additional","affiliation":[{"name":"Institute of Anatomy, Histology, and Pathology, Faculty of Medicine, Universidad Austral de Chile, 5090000 Valdivia, Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2519-7570","authenticated-orcid":false,"given":"Pamela","family":"Ehrenfeld","sequence":"additional","affiliation":[{"name":"Institute of Anatomy, Histology, and Pathology, Faculty of Medicine, Universidad Austral de Chile, 5090000 Valdivia, Chile"},{"name":"Center for Interdisciplinary Studies of the Nervous System [CISNe], Universidad Austral de Chile, 5090000 Valdivia, Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8232-1179","authenticated-orcid":false,"given":"Gernot","family":"L\u00e4ngst","sequence":"additional","affiliation":[{"name":"Regensburg Center for Biochemistry [RCB], Universit\u00e4t Regensburg, 93053 Regensburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4648-6697","authenticated-orcid":false,"given":"Rodrigo","family":"Maldonado","sequence":"additional","affiliation":[{"name":"Facultad de Medicina y Ciencias, Universidad San Sebasti\u00e1n, 5110246 Valdivia, Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,5,18]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Marchese, F.P., Raimondi, I., and Huarte, M. 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