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Whilst upstream signalling pathways leading to RBM3 expression have been described, the precise molecular mechanism of RBM3 cold induction remains elusive. To identify temperature\u2010dependent modulators of RBM3, we performed a genome\u2010wide CRISPR\u2010Cas9 knockout screen using RBM3\u2010reporter human iPSC\u2010derived neurons. We found that RBM3 mRNA and protein levels are robustly regulated by several splicing factors, with heterogeneous nuclear ribonucleoprotein H1 (HNRNPH1) being the strongest positive regulator. Splicing analysis revealed that moderate hypothermia significantly represses the inclusion of a poison exon, which, when retained, targets the mRNA for nonsense\u2010mediated decay. Importantly, we show that HNRNPH1 mediates this cold\u2010dependent exon skipping via its thermosensitive interaction with a G\u2010rich motif within the poison exon. Our study provides novel mechanistic insights into the regulation of RBM3 and provides further targets for neuroprotective therapeutic strategies.\n                  <\/jats:p>","DOI":"10.15252\/embj.2022113168","type":"journal-article","created":{"date-parts":[[2023,5,30]],"date-time":"2023-05-30T04:04:51Z","timestamp":1685419491000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":28,"title":["HNRNPH1 regulates the neuroprotective cold\u2010shock protein RBM3 expression through poison exon exclusion"],"prefix":"10.1038","volume":"42","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2669-6478","authenticated-orcid":false,"given":"Julie Qiaojin","family":"Lin","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4272-3034","authenticated-orcid":false,"given":"Deepak","family":"Khuperkar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sofia","family":"Pavlou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5484-7141","authenticated-orcid":false,"given":"Stanislaw","family":"Makarchuk","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3978-0134","authenticated-orcid":false,"given":"Nikolaos","family":"Patikas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3216-9754","authenticated-orcid":false,"given":"Flora CY","family":"Lee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6368-4599","authenticated-orcid":false,"given":"Julia M","family":"Zbiegly","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5259-2891","authenticated-orcid":false,"given":"Jianning","family":"Kang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah F","family":"Field","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David MD","family":"Bailey","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joshua L","family":"Freeman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2452-4277","authenticated-orcid":false,"given":"Jernej","family":"Ule","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2893-9741","authenticated-orcid":false,"given":"Emmanouil","family":"Metzakopian","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3264-9800","authenticated-orcid":false,"given":"Marc\u2010David","family":"Ruepp","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8504-1191","authenticated-orcid":false,"given":"Giovanna R","family":"Mallucci","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2023,5,30]]},"reference":[{"key":"BFEMBJ2022113168_CR1","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1016\/j.gde.2017.10.010","volume":"48","author":"AA Agrawal","year":"2018","unstructured":"Agrawal AA, Yu L, Smith PG, Buonamici S (2018) Targeting splicing abnormalities in cancer. 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