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We present here a computational approach named DExTER (Domain Exploration To Explain gene Regulation) dedicated to the identification of candidate LREs (cLREs) and apply it to the analysis of the genomes of\n                    <jats:italic>P<\/jats:italic>\n                    .\n                    <jats:italic>falciparum<\/jats:italic>\n                    and other eukaryotes. Our analyses show that all tested genomes contain several cLREs that are somewhat conserved along evolution, and that gene expression can be predicted with surprising accuracy on the basis of these long regions only. Regulation by cLREs exhibits very different behaviours depending on species and conditions. In\n                    <jats:italic>P<\/jats:italic>\n                    .\n                    <jats:italic>falciparum<\/jats:italic>\n                    and other Apicomplexan organisms as well as in\n                    <jats:italic>Dictyostelium discoideum<\/jats:italic>\n                    , the process appears highly dynamic, with different cLREs involved at different phases of the life cycle. For multicellular organisms, the same cLREs are involved in all tissues, but a dynamic behavior is observed along embryonic development stages. In\n                    <jats:italic>P<\/jats:italic>\n                    .\n                    <jats:italic>falciparum<\/jats:italic>\n                    , whose genome is known to be strongly depleted of transcription factors, cLREs are predictive of expression with an accuracy above 70%, and our analyses show that they are associated with both transcriptional and post-transcriptional regulation signals. Moreover, we assessed the biological relevance of one LRE discovered by DExTER in\n                    <jats:italic>P<\/jats:italic>\n                    .\n                    <jats:italic>falciparum<\/jats:italic>\n                    using an\n                    <jats:italic>in vivo<\/jats:italic>\n                    reporter assay.\n                  <\/jats:p>\n                  <jats:p>\n                    The source code (python) of DExTER is available at\n                    <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"uri\" xlink:href=\"https:\/\/gite.lirmm.fr\/menichelli\/DExTER\" xlink:type=\"simple\">https:\/\/gite.lirmm.fr\/menichelli\/DExTER<\/jats:ext-link>\n                    .\n                  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M.","family":"Martins","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3444-2416","authenticated-orcid":true,"given":"Sophie","family":"L\u00e8bre","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0555-1122","authenticated-orcid":true,"given":"Jose-Juan","family":"Lopez-Rubio","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0229-5434","authenticated-orcid":true,"given":"Charles-Henri","family":"Lecellier","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2582-2831","authenticated-orcid":true,"given":"Laurent","family":"Br\u00e9h\u00e9lin","sequence":"additional","affiliation":[]}],"member":"340","published-online":{"date-parts":[[2021,4,16]]},"reference":[{"issue":"4","key":"pcbi.1008909.ref001","doi-asserted-by":"crossref","first-page":"557","DOI":"10.1016\/j.chom.2018.03.007","article-title":"Chromatin Accessibility-Based Characterization of the 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