气候变化领域集成服务门户(CCPortal): DOT1L complex regulates transcriptional initiation in human erythroleukemic cells

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DOI	10.1073/pnas.2106148118
	DOT1L complex regulates transcriptional initiation in human erythroleukemic cells
	Wu A.; Zhi J.; Tian T.; Cihan A.; Cevher M.A.; Liu Z.; David Y.; Muir T.W.; Roeder R.G.; Yu M.
发表日期	2021
ISSN	0027-8424
卷号	118 期号:27
英文摘要	DOT1L, 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. © 2021 National Academy of Sciences. All rights reserved.
英文关键词	DOT1L complex; H2B monoubiquitination; SAGA; TFIID; Transcriptional initiation
语种	英语
scopus关键词	deubiquitinase; DOT1L; E1A associated p300 protein; histone H2B; histone H3; Myc protein; RNA polymerase; RNA polymerase II; TATA binding protein; transcription factor IIA; transcription factor IIB; transcription factor IID; transcription factor SAGA; unclassified drug; DOT1L protein, human; ELL protein, human; histone; histone lysine methyltransferase; protein binding; RNA polymerase II; transcription elongation factor; transcription factor IID; alternative RNA splicing; Article; chromatin assembly and disassembly; chromatin immunoprecipitation; coimmunoprecipitation; deubiquitination; erythroleukemic cell; gene editing; gene expression; gene rearrangement; human; human cell; immunoprecipitation; K-562 cell line; leukemia; mass spectrometry; nucleosome; polyacrylamide gel electrophoresis; protein expression; protein interaction; protein protein interaction; RNA splicing; transcription elongation; transcription initiation; transcription regulation; transcription termination; yeast; chromatin; erythroleukemia; gene expression regulation; genetics; metabolism; tumor cell line; ubiquitination; Cell Line, Tumor; Chromatin; Gene Expression Regulation, Leukemic; Histone-Lysine N-Methyltransferase; Histones; Humans; Leukemia, Erythroblastic, Acute; Protein Binding; RNA Polymerase II; Transcription Elongation, Genetic; Transcription Factor TFIID; Transcription Initiation, Genetic; Transcriptional Elongation Factors; Ubiquitination
来源期刊	Proceedings of the National Academy of Sciences of the United States of America
文献类型	期刊论文
条目标识符	http://gcip.llas.ac.cn/handle/2XKMVOVA/251139
作者单位	Sheng Yushou Center of Cell Biology and Immunology, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, 200240, China; Laboratory of Biochemistry and Molecular Biology, The Rockefeller University, New York, NY 10065, United States; Department of Molecular Biology and Genetics, Bilkent University, Ankara, 06800, Turkey; Department of Chemistry, Princeton University, Princeton, NJ 08540, United States; Ministry of Education Key Laboratory of Systems Biomedicine, Shanghai Jiao Tong University, Shanghai, 200240, China
推荐引用方式 GB/T 7714	Wu A.,Zhi J.,Tian T.,et al. DOT1L complex regulates transcriptional initiation in human erythroleukemic cells[J],2021,118(27).
APA	Wu A..,Zhi J..,Tian T..,Cihan A..,Cevher M.A..,...&Yu M..(2021).DOT1L complex regulates transcriptional initiation in human erythroleukemic cells.Proceedings of the National Academy of Sciences of the United States of America,118(27).
MLA	Wu A.,et al."DOT1L complex regulates transcriptional initiation in human erythroleukemic cells".Proceedings of the National Academy of Sciences of the United States of America 118.27(2021).