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Activation of Cyclin E\/Cdk2 at the G1-S transition stimulates high-level expression of histone genes during S phase, but how histone genes are turned off at the end of S phase is not understood. Here we demonstrate that the essential\n                    <jats:italic>Drosophila<\/jats:italic>\n                    gene\n                    <jats:italic>mute<\/jats:italic>\n                    functions to repress inappropriate histone mRNA accumulation outside of S phase by counteracting Cyclin E\/Cdk2-dependent phosphorylation of Mxc, which activates histone gene expression. Additionally, Mute plays contrasting roles in histone gene expression during S phase by promoting high levels of\n                    <jats:italic>H1<\/jats:italic>\n                    ,\n                    <jats:italic>H2a<\/jats:italic>\n                    , and\n                    <jats:italic>H2b<\/jats:italic>\n                    expression but not\n                    <jats:italic>H3<\/jats:italic>\n                    and\n                    <jats:italic>H4<\/jats:italic>\n                    . Although Mute is present only at replication-dependent histone genes, its loss leads to 801 differentially expressed genes, primarily those involved in muscle related processes in late-stage embryos. Thus, disruptions of histone gene expression control alter the transcriptome resulting in developmental defects.\n                  <\/jats:p>","DOI":"10.1101\/gad.353837.126","type":"journal-article","created":{"date-parts":[[2026,8,12]],"date-time":"2026-08-12T15:50:18Z","timestamp":1786549818000},"page":"1649-1668","source":"Crossref","is-referenced-by-count":1,"title":["Differential control of both cell cycle-regulated and quantitative histone mRNA expression by\n                    <i>Drosophila<\/i>\n                    Mute"],"prefix":"10.1101","volume":"40","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2900-4609","authenticated-orcid":false,"given":"Mark S.","family":"Geisler","sequence":"first","affiliation":[{"name":"Curriculum in Genetics and Molecular Biology, University of North Carolina, Chapel Hill, North Carolina 27599, USA;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1975-1149","authenticated-orcid":false,"suffix":"Jr.","given":"James P.","family":"Kemp","sequence":"additional","affiliation":[{"name":"Integrative Program for Biological and Genome Sciences, University of North Carolina, Chapel Hill, North Carolina 27599, USA;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christina A.","family":"Hill","sequence":"additional","affiliation":[{"name":"Integrative Program for Biological and Genome Sciences, University of North Carolina, Chapel Hill, North Carolina 27599, USA;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3635-4073","authenticated-orcid":false,"given":"William F.","family":"Marzluff","sequence":"additional","affiliation":[{"name":"Curriculum in Genetics and Molecular Biology, University of North Carolina, Chapel Hill, North Carolina 27599, USA;"},{"name":"Integrative Program for Biological and Genome Sciences, University of North Carolina, Chapel Hill, North Carolina 27599, USA;"},{"name":"Department of Biology, University of North Carolina, Chapel Hill, North Carolina 27599, USA;"},{"name":"Department of Biochemistry and Biophysics, University of North Carolina, Chapel Hill, North Carolina 27599, USA;"},{"name":"Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina 27599, USA;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6469-6965","authenticated-orcid":false,"given":"Robert J.","family":"Duronio","sequence":"additional","affiliation":[{"name":"Curriculum in Genetics and Molecular Biology, University of North Carolina, Chapel Hill, North Carolina 27599, USA;"},{"name":"Integrative Program for Biological and Genome Sciences, University of North Carolina, Chapel Hill, North Carolina 27599, USA;"},{"name":"Department of Biology, University of North Carolina, Chapel Hill, North Carolina 27599, USA;"},{"name":"Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina 27599, USA;"},{"name":"Department of Genetics, University of North Carolina, Chapel Hill, North Carolina 27599, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"246","published-online":{"date-parts":[[2026,8,12]]},"reference":[{"key":"2026100108250955000_40.19-20.1649.1","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-16-1099"},{"key":"2026100108250955000_40.19-20.1649.2","doi-asserted-by":"publisher","DOI":"10.1038\/s41594-025-01731-1"},{"key":"2026100108250955000_40.19-20.1649.3","doi-asserted-by":"publisher","DOI":"10.1261\/rna.079931.123"},{"key":"2026100108250955000_40.19-20.1649.4","unstructured":"Alberts B , Johnson A , Lewis J , Raff M , Roberts K , Walter P . 2002. 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