{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T09:36:41Z","timestamp":1785404201412,"version":"3.56.0"},"posted":{"date-parts":[[2026,4,18]]},"group-title":"Molecular Biology","reference-count":60,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,4,18]],"date-time":"2026-04-18T00:00:00Z","timestamp":1776470400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"award":["R01HL119479"],"award-info":[{"award-number":["R01HL119479"]}],"id":[{"id":"https:\/\/ror.org\/012pb6c26","id-type":"ROR","asserted-by":"publisher"}]},{"award":["F30HL178209"],"award-info":[{"award-number":["F30HL178209"]}],"id":[{"id":"https:\/\/ror.org\/012pb6c26","id-type":"ROR","asserted-by":"publisher"}]},{"award":["R01DK058044"],"award-info":[{"award-number":["R01DK058044"]}],"id":[{"id":"https:\/\/ror.org\/00adh9b73","id-type":"ROR","asserted-by":"publisher"}]},{"award":["R01DK054937"],"award-info":[{"award-number":["R01DK054937"]}],"id":[{"id":"https:\/\/ror.org\/00adh9b73","id-type":"ROR","asserted-by":"publisher"}]},{"award":["T32DK007780"],"award-info":[{"award-number":["T32DK007780"]}],"id":[{"id":"https:\/\/ror.org\/00adh9b73","id-type":"ROR","asserted-by":"publisher"}]},{"award":["TL1DK143326"],"award-info":[{"award-number":["TL1DK143326"]}],"id":[{"id":"https:\/\/ror.org\/00adh9b73","id-type":"ROR","asserted-by":"publisher"}]},{"award":["DK106829"],"award-info":[{"award-number":["DK106829"]}],"id":[{"id":"https:\/\/ror.org\/00adh9b73","id-type":"ROR","asserted-by":"publisher"}]},{"DOI":"10.13039\/100007737","name":"St. Jude Children's Research Hospital","doi-asserted-by":"crossref","award":["Collaborative research consortium for novel gene therapies on sickle cell disease"],"award-info":[{"award-number":["Collaborative research consortium for novel gene therapies on sickle cell disease"]}],"id":[{"id":"10.13039\/100007737","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,4,18]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Polycomb repressive complexes PRC1 and PRC2 regulate diverse developmental processes, including the fetal-to-adult switch in hemoglobin production, a process whose reversal is a goal for the treatment of sickle cell disease and \u03b2-thalassemia. PRC inhibitors show promise for various disorders, but use is limited because of pleiotropic PRC activities. We explored whether fetal hemoglobin (HbF) can be reactivated in adult erythroid cells by selective perturbations of PRC1 or PRC2 components without complete loss of PRC function. A high-density CRISPR-Cas9 mutagenesis screen identified a region in the\n                  <jats:italic>EZH2<\/jats:italic>\n                  subunit where Cas9 induced exon 14 skipping (EZH2\u039414). EZH2\u039414, which lacks a portion of the CXC domain, relieves HbF repression while largely maintaining cellular fitness. EZH2\u039414 retains H3K27 methylation and repression of a PRC target gene subset. Experiments in cells derived from mice bearing human \u03b2-globin genes confirm that pathways mediating EZH2 control of HbF expression can function in a mouse model of\n                  <jats:italic>HBG<\/jats:italic>\n                  switching. These findings demonstrate that partial disruption of PRC can yield selective phenotypes, highlighting the therapeutic potential of targeting non-enzymatic domains within chromatin-modifying complexes.\n                <\/jats:p>\n                <jats:sec>\n                  <jats:title>Key Points<\/jats:title>\n                  <jats:list list-type=\"bullet\">\n                    <jats:list-item>\n                      <jats:p>CRISPR-Cas9 screen across PRC1 and a saturating mutagenesis screen of PRC2 found the EZH2 CXC domain a desirable target for HbF induction<\/jats:p>\n                    <\/jats:list-item>\n                    <jats:list-item>\n                      <jats:p>the EZH2-CXC domain leads to exon 14 exclusion, resulting in de-repression of HbF but maintenance of cell fitness.<\/jats:p>\n                    <\/jats:list-item>\n                  <\/jats:list>\n                <\/jats:sec>","DOI":"10.64898\/2026.04.16.718974","type":"posted-content","created":{"date-parts":[[2026,4,18]],"date-time":"2026-04-18T17:35:18Z","timestamp":1776533718000},"source":"Crossref","is-referenced-by-count":0,"title":["Dissecting polycomb complexes for enhanced fetal hemoglobin production"],"prefix":"10.64898","author":[{"given":"Paul J.","family":"Kaminski","sequence":"first","affiliation":[{"name":"Division of Hematology, Children\u2019s Hospital of Philadelphia, Philadelphia, PA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kristen","family":"Min","sequence":"additional","affiliation":[{"name":"Division of Hematology, Children\u2019s Hospital of Philadelphia, Philadelphia, PA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elizabeth A.","family":"Traxler","sequence":"additional","affiliation":[{"name":"Division of Hematology and Oncology, University of Pennsylvania, Philadelphia, PA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eugene","family":"Khandros","sequence":"additional","affiliation":[{"name":"Division of Hematology, Children\u2019s Hospital of Philadelphia, Philadelphia, PA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Osheiza","family":"Abdulmalik","sequence":"additional","affiliation":[{"name":"Division of Hematology, Children\u2019s Hospital of Philadelphia, Philadelphia, PA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bailey","family":"Godfrey","sequence":"additional","affiliation":[{"name":"Division of Hematology, Children\u2019s Hospital of Philadelphia, Philadelphia, PA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6594-0245","authenticated-orcid":false,"given":"Cheryl A.","family":"Keller","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Pennsylvania State University, University Park, State College, PA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Belinda M.","family":"Giardine","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Pennsylvania State University, University Park, State College, PA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4084-7516","authenticated-orcid":false,"given":"Ross C.","family":"Hardison","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Pennsylvania State University, University Park, State College, PA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junwei","family":"Shi","sequence":"additional","affiliation":[{"name":"Department of Cancer Biology, University of Pennsylvania, Philadelphia, PA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gerd A.","family":"Blobel","sequence":"additional","affiliation":[{"name":"Division of Hematology, Children\u2019s Hospital of Philadelphia, Philadelphia, PA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026042112051034000_2026.04.16.718974v1.1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM199406093302303"},{"key":"2026042112051034000_2026.04.16.718974v1.2","doi-asserted-by":"crossref","unstructured":"Uda M , Galanello R , Sanna S , et al. 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