DOT1L complex regulates transcriptional initiation in human erythroleukemic cells

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buir.contributor.authorCevher, Murat Alper
buir.contributor.orcidCevher, Murat Alper|0000-0002-2663-1172
dc.citation.epage10en_US
dc.citation.issueNumber27en_US
dc.citation.spage1en_US
dc.citation.volumeNumber118en_US
dc.contributor.authorWu, A.
dc.contributor.authorZhi, J.
dc.contributor.authorTian, T.
dc.contributor.authorCihan, A.
dc.contributor.authorCevher, Murat Alper
dc.contributor.authorLiu, Z.
dc.contributor.authorDavid, Y.
dc.contributor.authorMuir, T. W.
dc.contributor.authorRoeder, R. G.
dc.contributor.authorYu, M.
dc.date.accessioned2022-02-14T13:31:13Z
dc.date.available2022-02-14T13:31:13Z
dc.date.issued2021-06-29
dc.departmentDepartment of Molecular Biology and Geneticsen_US
dc.description.abstractDOT1L, the only H3K79 methyltransferase in human cells and a homolog of the yeast Dot1, normally forms a complex with AF10, AF17, and ENL or AF9, is dysregulated in most cases of mixed-lineage leukemia (MLLr), and has been believed to regulate transcriptional elongation on the basis of its colocalization with RNA polymerase II (Pol II), the sharing of subunits (AF9 and ENL) between the DOT1L and super elongation complexes, and the distribution of H3K79 methylation on both promoters and transcribed regions of active genes. Here we show that DOT1L depletion in erythroleukemic cells reduces its global occupancy without affecting the traveling ratio or the elongation rate (assessed by 4sUDRB-seq) of Pol II, suggesting that DOT1L does not play a major role in elongation in these cells. In contrast, analyses of transcription initiation factor binding reveal that DOT1L and ENL depletions each result in reduced TATA binding protein (TBP) occupancies on thousands of genes. More importantly, DOT1L and ENL depletions concomitantly reduce TBP and Pol II occupancies on a significant fraction of direct (DOT1L-bound) target genes, indicating a role for the DOT1L complex in transcription initiation. Mechanistically, proteomic and biochemical studies suggest that the DOT1L complex may regulate transcriptional initiation by facilitating the recruitment or stabilization of transcription factor IID, likely in a monoubiquitinated H2B (H2Bub1)-enhanced manner. Additional studies show that DOT1L enhances H2Bub1 levels by limiting recruitment of the Spt-Ada-Gcn5-acetyltransferase (SAGA) complex. These results advance our understanding of roles of the DOT1L complex in transcriptional regulation and have important implications for MLLr leukemias.en_US
dc.identifier.doi10.1073/pnas.2106148118en_US
dc.identifier.eissn1091-6490
dc.identifier.issn0027-8424
dc.identifier.urihttp://hdl.handle.net/11693/77334
dc.language.isoEnglishen_US
dc.publisherNational Academy of Sciencesen_US
dc.relation.isversionofhttps://doi.org/10.1073/pnas.2106148118en_US
dc.source.titleProceedings of the National Academy of Sciences of the United States of Americaen_US
dc.subjectDOT1L complexen_US
dc.subjectTranscriptional initiationen_US
dc.subjectTFIIDen_US
dc.subjectSAGAen_US
dc.subjectH2B monoubiquitinationen_US
dc.titleDOT1L complex regulates transcriptional initiation in human erythroleukemic cellsen_US
dc.typeArticleen_US

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