{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T11:59:25Z","timestamp":1791460765017,"version":"4.3.4"},"posted":{"date-parts":[[2026,10,4]]},"group-title":"Molecular Biology","reference-count":59,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,10,4]],"date-time":"2026-10-04T00:00:00Z","timestamp":1791072000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.biorxiv.org\/about\/FAQ#license"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,10,4]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:p>\n                  Pitt-Hopkins syndrome (PTHS) is a severe neurodevelopmental disorder caused by haploinsufficient expression of transcription factor 4 (\n                  <jats:italic>TCF4<\/jats:italic>\n                  ). Increasing expression from the remaining functional\n                  <jats:italic>TCF4<\/jats:italic>\n                  allele could provide a mutation-independent strategy for patients with diverse pathogenic variants. We integrated genomic datasets with strand-specific RNA analysis to identify transcribed regions of the\n                  <jats:italic>TCF4<\/jats:italic>\n                  promoter suitable for targeting by activating double-stranded RNAs (dsRNAs). Screening of overlapping promoter-targeted dsRNAs identified a hotspot for increased\n                  <jats:italic>TCF4<\/jats:italic>\n                  expression. Activation was retained by a lead dsRNA containing extensive 2\u2032-fluoro, 2\u2032-O-methyl, and phosphorothioate modifications used in therapeutic oligonucleotides. Anti-AGO2 immunoprecipitation showed association with RNA transcribed from the targeted promoter region. dsRNA-mediated activation was associated with increased RNA polymerase II occupancy. These findings establish promoter-targeted dsRNAs as chemically tractable starting points for increasing\n                  <jats:italic>TCF4<\/jats:italic>\n                  expression and support their investigation as a mutation-independent strategy for haploinsufficient disease.\n                <\/jats:p>","DOI":"10.64898\/2026.10.02.756310","type":"posted-content","created":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T03:15:12Z","timestamp":1791170112000},"source":"Crossref","is-referenced-by-count":0,"title":["A chemically modified promoter-targeted duplex RNA activates\n                  <i>TCF4<\/i>\n                  expression"],"prefix":"10.64898","author":[{"given":"Bethany A.","family":"Janowski","sequence":"first","affiliation":[{"name":"Departments of Pharmacology and Biochemistry, UT Southwestern Medical Center, 6001 Forest Park Lane, Dallas, TX 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