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While these pH-sensitive structures are unlikely to govern gene expression in normal tissues, their contribution to acidosis-specific transcriptional reprogramming cannot be ruled out. Here, we focused on previously reported iM-forming sequences from the regulatory regions of early response genes. We tested their impact on transcription via luciferase-based assays under normal conditions, as well as under conditions favoring or disfavoring iMs (acidic media or iM-destabilizing ligands, respectively). We verified and elucidated the effects of pH and ligands by optical methods and molecular modeling, respectively. Our data indicate that iMs tend to repress reporter gene expression in response to acidification, and this effect could be reversed by selective ligands, including an anticancer drug candidate. These results highlight the potential of targeting iMs to mitigate the pathogenic response to acidosis.<\/jats:p>","DOI":"10.3390\/biom16071038","type":"journal-article","created":{"date-parts":[[2026,7,16]],"date-time":"2026-07-16T09:23:14Z","timestamp":1784193794000},"page":"1038","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Intercalated Motifs Contribute to Transcription Regulation in an Acidosis Model"],"prefix":"10.3390","volume":"16","author":[{"given":"Varvara","family":"Sapozhnikova","sequence":"first","affiliation":[{"name":"Lopukhin Federal Research and Clinical Center of Physical-Chemical Medicine of Federal Medical Biological Agency, 119435 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ekaterina","family":"Knizhnik","sequence":"additional","affiliation":[{"name":"Lopukhin Federal Research and Clinical Center of Physical-Chemical Medicine of Federal Medical Biological Agency, 119435 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6080-3348","authenticated-orcid":false,"given":"Dmitriy","family":"Shirokov","sequence":"additional","affiliation":[{"name":"Lopukhin Federal Research and Clinical Center of Physical-Chemical Medicine of Federal Medical Biological Agency, 119435 Moscow, Russia"},{"name":"K.I. Skryabin Moscow State Academy of Veterinary Medicine and Biotechnology, 109472 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0162-4857","authenticated-orcid":false,"given":"Yuri","family":"Khodarovich","sequence":"additional","affiliation":[{"name":"Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, 117997 Moscow, Russia"},{"name":"Research and Educational Resource Center for Cellular Technologies of the Peoples\u2019 Friendship University of Russia, 117198 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julia","family":"Khomyakova","sequence":"additional","affiliation":[{"name":"Lopukhin Federal Research and Clinical Center of Physical-Chemical Medicine of Federal Medical Biological Agency, 119435 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Margarita","family":"Bogomiakova","sequence":"additional","affiliation":[{"name":"Lopukhin Federal Research and Clinical Center of Physical-Chemical Medicine of Federal Medical Biological Agency, 119435 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6418-1539","authenticated-orcid":false,"given":"Alexander","family":"Tikhomirov","sequence":"additional","affiliation":[{"name":"Gause Institute of New Antibiotics, 119021 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6595-0811","authenticated-orcid":false,"given":"Andrey","family":"Shchekotikhin","sequence":"additional","affiliation":[{"name":"Gause Institute of New Antibiotics, 119021 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9359-8651","authenticated-orcid":false,"given":"Anna","family":"Varizhuk","sequence":"additional","affiliation":[{"name":"Lopukhin Federal Research and Clinical Center of Physical-Chemical Medicine of Federal Medical Biological Agency, 119435 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0494-3332","authenticated-orcid":false,"given":"Vladimir","family":"Tsvetkov","sequence":"additional","affiliation":[{"name":"Lopukhin Federal Research and Clinical Center of Physical-Chemical Medicine of Federal Medical Biological Agency, 119435 Moscow, Russia"},{"name":"A. V. Topchiev Institute of Petrochemical Synthesis RAS, 119991 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,16]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"561","DOI":"10.1038\/363561a0","article-title":"A Tetrameric DNA Structure with Protonated Cytosine-Cytosine Base Pairs","volume":"363","author":"Gehring","year":"1993","journal-title":"Nature"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"8038","DOI":"10.1093\/nar\/gky735","article-title":"I-Motif DNA: Structural Features and Significance to Cell Biology","volume":"46","author":"Damha","year":"2018","journal-title":"Nucleic Acids Res."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"4067","DOI":"10.1002\/anie.201200549","article-title":"The Nature of Hydrogen Bonds in Cytidine\u22c5\u22c5\u22c5H + \u22c5\u22c5\u22c5Cytidine DNA Base Pairs","volume":"51","author":"Lieblein","year":"2012","journal-title":"Angew. 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