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Interferon gamma (IFN-\u03b3) from immune cells infiltrated at the site of infection plays a key role in the epithelial cell-intrinsic defense. Nevertheless, the success of the parasite is the result of its ability to evade the host immune responses. Increasing evidence suggests that long noncoding RNAs (lncRNA) participate in host-pathogen interactions, but the underlying mechanisms are not fully understood. We previously demonstrated that lncRNA U90926 is upregulated in response to infection but appears to be playing a pro-parasitic role given its ability to repress transcription of defense genes and aid the parasite during infection. We show here that inhibition of U90926 during\n                      <jats:italic toggle=\"yes\">Cryptosporidium<\/jats:italic>\n                      infection increased expressions of\n                      <jats:italic toggle=\"yes\">Irgm2<\/jats:italic>\n                      ,\n                      <jats:italic toggle=\"yes\">Igtp<\/jats:italic>\n                      , and\n                      <jats:italic toggle=\"yes\">Iigp1<\/jats:italic>\n                      , which are known IFN-\u03b3-stimulated genes, in a gene-specific manner. Depletion of U90926 results in an increase in histone modifications associated with gene transactivation in the promoter regions of\n                      <jats:italic toggle=\"yes\">Irgm2<\/jats:italic>\n                      ,\n                      <jats:italic toggle=\"yes\">Igtp<\/jats:italic>\n                      , and\n                      <jats:italic toggle=\"yes\">Ilgp1<\/jats:italic>\n                      , suggesting U90926 is regulating defense gene expression via epigenetic modifications. U90926 can interact with Ehmt2, a potent euchromatic methyltransferase, in the promoter region of these defense genes to alter histone modifications. Knockout of U90926 enhances IFN-\u03b3-mediated inhibition of\n                      <jats:italic toggle=\"yes\">Cryptosporidium<\/jats:italic>\n                      infection, suggesting that U90926 may modulate IFN-\u03b3-induced gene expression to suppress cell-intrinsic antimicrobial defenses. The data highlight a strategy\n                      <jats:italic toggle=\"yes\">Cryptosporidium<\/jats:italic>\n                      has evolved to hijack host cell lncRNA machinery to suppress the immune response and allow for a robust infection.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1128\/iai.00328-25","type":"journal-article","created":{"date-parts":[[2025,9,22]],"date-time":"2025-09-22T15:06:09Z","timestamp":1758553569000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":2,"title":["Long non-coding RNA U90926 modulates IFN-\u03b3-stimulated gene transcription and cell-intrinsic anti-\n                    <i>Cryptosporidium<\/i>\n                    defense in intestinal epithelial cells"],"prefix":"10.1128","volume":"93","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9445-9896","authenticated-orcid":false,"given":"Marion 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