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Previous research, including our own, has shown that small RNA products of the Chromosome 19 MicroRNA Cluster (C19MC) promote viral resistance in non-trophoblastic cells. However, the role of C19MC products in placental trophoblasts remained unclear. Here, we analyzed chromatin accessibility in the C19MC enhancer and identified a previously unknown regulatory domain. Deletion of this domain silenced the expression of C19MC microRNA and Alu elements in trophoblasts. This silencing unexpectedly led to marked activation of cellular innate immune response and strikingly increased Toll-like receptor 3 (TLR3)-mediated sensitivity to poly(I:C), a viral RNA mimic. Our data suggest that C19MC non-coding RNAs interfere with endosomal TLR3 activation in trophoblasts, highlighting a previously unrecognized mechanism for hindrance of excessive innate immune activation.<\/jats:p>","DOI":"10.1101\/2025.04.03.647038","type":"posted-content","created":{"date-parts":[[2025,4,5]],"date-time":"2025-04-05T18:05:11Z","timestamp":1743876311000},"source":"Crossref","is-referenced-by-count":0,"title":["The Chromosome 19 miRNA Cluster Guards Trophoblasts Against Overacting Innate Immunity"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9816-0579","authenticated-orcid":false,"given":"Jean-Francois","family":"Mouillet","sequence":"first","affiliation":[{"name":"Magee-Womens Research Institute, Department of Obstetrics, Gynecology and Reproductive Sciences, University of Pittsburgh, Pittsburgh, PA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8970-1297","authenticated-orcid":false,"given":"Yingshi","family":"Ouyang","sequence":"additional","affiliation":[{"name":"Magee-Womens Research Institute, Department of Obstetrics, Gynecology and Reproductive Sciences, University of Pittsburgh, Pittsburgh, PA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elena","family":"Sadovsky","sequence":"additional","affiliation":[{"name":"Magee-Womens Research Institute, Department of Obstetrics, Gynecology and Reproductive Sciences, University of Pittsburgh, Pittsburgh, PA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6359-6989","authenticated-orcid":false,"given":"Vinoth K.","family":"Kothnadan","sequence":"additional","affiliation":[{"name":"Magee-Womens Research Institute, Department of Obstetrics, Gynecology and Reproductive Sciences, University of Pittsburgh, Pittsburgh, PA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heather L.","family":"Sorenson","sequence":"additional","affiliation":[{"name":"Magee-Womens Research Institute, Department of Obstetrics, Gynecology and Reproductive Sciences, University of Pittsburgh, Pittsburgh, PA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-8735-0991","authenticated-orcid":false,"given":"Logan J.","family":"Badeau","sequence":"additional","affiliation":[{"name":"Magee-Womens Research Institute, Department of Obstetrics, Gynecology and Reproductive Sciences, University of Pittsburgh, Pittsburgh, PA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2850-6121","authenticated-orcid":false,"given":"Saumendra N.","family":"Sarkar","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, MD, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9644-771X","authenticated-orcid":false,"given":"Tianjiao","family":"Chu","sequence":"additional","affiliation":[{"name":"Magee-Womens Research Institute, Department of Obstetrics, Gynecology and Reproductive Sciences, University of Pittsburgh, Pittsburgh, PA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4446-1920","authenticated-orcid":false,"given":"Alexander","family":"Sorkin","sequence":"additional","affiliation":[{"name":"Department of Cell Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2969-6737","authenticated-orcid":false,"given":"Yoel","family":"Sadovsky","sequence":"additional","affiliation":[{"name":"Magee-Womens Research Institute, Department of Obstetrics, Gynecology and Reproductive Sciences, University of Pittsburgh, Pittsburgh, PA, USA"},{"name":"Department of Microbiology and Molecular Genetics, University of Pittsburgh, Pittsburgh, PA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026041203432132000_2025.04.03.647038v2.1","doi-asserted-by":"crossref","unstructured":"Turco, M. 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