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To counteract viral antagonism, MORC3 represses a noncanonical pathway of type-I-interferon (IFN) such that viral inhibition of MORC3 triggers (\u2009&gt;\u200910,000-fold) IFN induction. How MORC3 represses this pathway, and why IFN induction upon MORC3 loss is so potent without canonical IRF3\/7 transcription factors, is unknown. Here, we show that MORC3 restricts chromatin accessibility at tandem repeat elements harboring up to 61 homotypic transcription factor motifs. One such element becomes a potent enhancer of\n                    <jats:italic>IFNB1<\/jats:italic>\n                    upon MORC3 loss. Its motif cluster contains 45 PU.1 binding sites and is necessary and sufficient for MORC3-mediated repression and enhancer activity upon MORC3 loss. PU.1 recruits MORC3 to repress this enhancer by recruiting DAXX and enabling H3.3 incorporation. Upon MORC3 loss, PU.1 drives IRF3\/7-independent IFN induction. Other restricted tandem repeats contain homotypic motif clusters of SPI, AP-1, and SP\/KLF transcription factors. Our findings uncover a TF motif cluster\u2013driven repression mechanism by MORC3 at tandem repeats, enabling specific repression of an IFNB1 enhancer such that viral antagonism of MORC3 induces interferon.\n                  <\/jats:p>","DOI":"10.1038\/s44318-026-00799-9","type":"journal-article","created":{"date-parts":[[2026,6,5]],"date-time":"2026-06-05T09:02:29Z","timestamp":1780650149000},"page":"5130-5163","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["MORC3 represses a tandem repeat enhancer to regulate interferon"],"prefix":"10.1038","volume":"45","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5695-1575","authenticated-orcid":false,"given":"Luisa","family":"Krumwiede","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7403-6434","authenticated-orcid":false,"given":"David","family":"Hollaus","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-4358-1403","authenticated-orcid":false,"given":"Erika","family":"Valeri","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karina","family":"Schindler-Schumitsch","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Monika A","family":"Bazyl","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Johanna","family":"Schiedlbauer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-4672-1107","authenticated-orcid":false,"given":"Nanette N","family":"Becht","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9326-2047","authenticated-orcid":false,"given":"Markus","family":"Jaritz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bernardo P","family":"de Almeida","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4574-8330","authenticated-orcid":false,"given":"Siegfried","family":"Schloissnig","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3856-0815","authenticated-orcid":false,"given":"Dara L","family":"Burdette","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jacob","family":"Schreiber","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2611-0841","authenticated-orcid":false,"given":"Alexander","family":"Stark","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8009-294X","authenticated-orcid":false,"given":"Moritz M","family":"Gaidt","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,6,5]]},"reference":[{"key":"799_CR1","doi-asserted-by":"publisher","first-page":"1196","DOI":"10.1038\/s41592-021-01252-x","volume":"18","author":"Z Avsec","year":"2021","unstructured":"Avsec Z, Agarwal V, Visentin D, Ledsam JR, Grabska-Barwinska A, Taylor KR, Assael Y, Jumper J, Kohli P, Kelley DR (2021a) Effective gene expression prediction from sequence by integrating long-range interactions. 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