{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T18:08:06Z","timestamp":1785434886763,"version":"3.56.0"},"reference-count":66,"publisher":"Public Library of Science (PLoS)","issue":"12","license":[{"start":{"date-parts":[[2025,12,17]],"date-time":"2025-12-17T00:00:00Z","timestamp":1765929600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"NIH","award":["NIGMS GM122524"],"award-info":[{"award-number":["NIGMS GM122524"]}]},{"name":"NIH","award":["NIGMS GM139960"],"award-info":[{"award-number":["NIGMS GM139960"]}]},{"name":"Boston Children's Hospital Office of Faculty Development"}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS One"],"abstract":"<jats:p>\n                    SF3B1, a component of the U2 snRNP pre-mRNA splicing factor, plays a critical role in splicing and is frequently mutated in cancer, particularly hematologic malignancies. We investigated the effects of the most common\n                    <jats:italic>SF3B1<\/jats:italic>\n                    mutation, heterozygous substitution of Lysine 700 to Glutamate (K700E), in human embryonic stem cells (hESC), using CRISPR-Cas9 to generate heterozygous\n                    <jats:italic>SF3B1<\/jats:italic>\n                    <jats:sup>\n                      <jats:italic>K700E<\/jats:italic>\n                    <\/jats:sup>\n                    clones. Interestingly, we observed the upregulation of several key transcription regulators associated with hematopoiesis and a broad range of immune genes in\n                    <jats:italic>SF3B1<\/jats:italic>\n                    <jats:sup>\n                      <jats:italic>K700E<\/jats:italic>\n                    <\/jats:sup>\n                    hESCs. Despite differences in the transcriptional and splicing profiles between hESC and myelodysplastic syndrome (MDS) cells harboring the\n                    <jats:italic>SF3B1<\/jats:italic>\n                    <jats:sup>\n                      <jats:italic>K700E<\/jats:italic>\n                    <\/jats:sup>\n                    mutation, several common immune gene programs were identified in both cell types. To elucidate the molecular mechanisms underlying dysregulated gene expression in\n                    <jats:italic>SF3B1<\/jats:italic>\n                    <jats:sup>\n                      <jats:italic>K700E<\/jats:italic>\n                    <\/jats:sup>\n                    hESCs, we mapped actively engaged RNA polymerase II (RNA Pol II) using Precision Run-On sequencing (PRO-seq). These analyses revealed that the\n                    <jats:italic>SF3B1<\/jats:italic>\n                    <jats:sup>\n                      <jats:italic>K700E<\/jats:italic>\n                    <\/jats:sup>\n                    mutation alters RNA Pol II elongation properties. Specifically, we observed a general increase in pause release in\n                    <jats:italic>SF3B1<\/jats:italic>\n                    <jats:sup>\n                      <jats:italic>K700E<\/jats:italic>\n                    <\/jats:sup>\n                    hESCs, consistent with recent work in leukemia cells suggesting that the\n                    <jats:italic>SF3B1<\/jats:italic>\n                    <jats:sup>\n                      <jats:italic>K700E<\/jats:italic>\n                    <\/jats:sup>\n                    mutation affects early transcription elongation. Taken together, our study identifies several candidate genes that could contribute to the\n                    <jats:italic>SF3B1<\/jats:italic>\n                    mutated phenotype and clarifies the role for the U2 snRNP and pre-spliceosome assembly on transcription by RNA Pol II. Further, our data suggest that mutations of\n                    <jats:italic>SF3B1<\/jats:italic>\n                    impact immune gene expression independent of cell type, providing new insights into the role of\n                    <jats:italic>SF3B1<\/jats:italic>\n                    <jats:sup>\n                      <jats:italic>K700E<\/jats:italic>\n                    <\/jats:sup>\n                    in hematologic malignancies.\n                  <\/jats:p>","DOI":"10.1371\/journal.pone.0334361","type":"journal-article","created":{"date-parts":[[2025,12,17]],"date-time":"2025-12-17T18:31:47Z","timestamp":1765996307000},"page":"e0334361","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":1,"title":["SF3B1K700E mutation in human embryonic stem cells causes aberrant expression of immune-related genes"],"prefix":"10.1371","volume":"20","author":[{"given":"Mahtab","family":"Dastpak","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claudia A.","family":"Mimoso","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Moein","family":"Farshchian","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8515-3126","authenticated-orcid":true,"given":"Christina L.","family":"Paraggio","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claudia E.","family":"Leonard","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shanye","family":"Yin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Binkai","family":"Chi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kelsey W.","family":"Nassar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"R. Grant","family":"Rowe","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiuchun","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhonggang","family":"Hou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"George Q.","family":"Daley","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5364-334X","authenticated-orcid":true,"given":"Karen","family":"Adelman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robin","family":"Reed","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2025,12,17]]},"reference":[{"issue":"9","key":"pone.0334361.ref001","doi-asserted-by":"crossref","first-page":"1285","DOI":"10.1261\/rna.057919.116","article-title":"Splicing-factor alterations in cancers","volume":"22","author":"O Anczuk\u00f3w","year":"2016","journal-title":"RNA"},{"key":"pone.0334361.ref002","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1186\/s40364-020-00220-5","article-title":"The biological function and clinical significance of SF3B1 mutations in cancer","volume":"8","author":"Z Zhou","year":"2020","journal-title":"Biomark Res"},{"issue":"3","key":"pone.0334361.ref003","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1038\/s41568-022-00541-7","article-title":"RNA splicing dysregulation and the hallmarks of cancer","volume":"23","author":"RK Bradley","year":"2023","journal-title":"Nat Rev Cancer"},{"issue":"2","key":"pone.0334361.ref004","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1038\/ng.2523","article-title":"Recurrent mutations at codon 625 of the splicing factor SF3B1 in uveal melanoma","volume":"45","author":"JW Harbour","year":"2013","journal-title":"Nat Genet"},{"issue":"5","key":"pone.0334361.ref005","doi-asserted-by":"crossref","first-page":"336","DOI":"10.1016\/j.tig.2017.03.001","article-title":"Splicing factor mutations in myelodysplasias: insights from spliceosome structures","volume":"33","author":"JL Jenkins","year":"2017","journal-title":"Trends Genet"},{"issue":"2","key":"pone.0334361.ref006","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1182\/blood.2020005719","article-title":"SF3B1: the lord of the rings in MDS","volume":"136","author":"L Palomo","year":"2020","journal-title":"Blood"},{"issue":"12","key":"pone.0334361.ref007","doi-asserted-by":"crossref","first-page":"1225","DOI":"10.1182\/blood-2018-04-843771","article-title":"Impact of spliceosome mutations on RNA splicing in myelodysplasia: dysregulated genes\/pathways and clinical associations","volume":"132","author":"A Pellagatti","year":"2018","journal-title":"Blood"},{"key":"pone.0334361.ref008","doi-asserted-by":"crossref","unstructured":"Wan Y, Wu CJ. 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