MLL-dependent network sustains hematopoiesis
The histone methyltransferase Mixed Lineage Leukemia (MLL) is essential to maintain hematopoietic stem cells and is a leukemia protooncogene. Although clustered homeobox genes are well-characterized targets of MLL and MLL fusion oncoproteins, the range of Mll -regulated genes in normal hematopoietic...
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| Veröffentlicht in: | Proceedings of the National Academy of Sciences - PNAS 2013-07, Vol.110 (29), p.12000-12005 |
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| container_title | Proceedings of the National Academy of Sciences - PNAS |
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| creator | Artinger, Erika L. Mishra, Bibhu P. Zaffuto, Kristin M. Li, Bin E. Chung, Elaine K. Y. Moore, Adrian W. Chen, Yufei Cheng, Chao Ernst, Patricia |
| description | The histone methyltransferase Mixed Lineage Leukemia (MLL) is essential to maintain hematopoietic stem cells and is a leukemia protooncogene. Although clustered homeobox genes are well-characterized targets of MLL and MLL fusion oncoproteins, the range of Mll -regulated genes in normal hematopoietic cells remains unknown. Here, we identify and characterize part of the Mll -dependent transcriptional network in hematopoietic stem cells with an integrated approach by using conditional loss-of-function models, genomewide expression analyses, chromatin immunoprecipitation, and functional rescue assays. The Mll -dependent transcriptional network extends well beyond the previously appreciated Hox targets, is comprised of many characterized regulators of self-renewal, and contains target genes that are both dependent and independent of the MLL cofactor, Menin. Interestingly, PR-domain containing 16 emerged as a target gene that is uniquely effective at partially rescuing Mll -deficient hematopoietic stem and progenitor cells. This work highlights the tissue-specific nature of regulatory networks under the control of MLL/Trithorax family members and provides insight into the distinctions between the participation of MLL in normal hematopoiesis and in leukemia. |
| doi_str_mv | 10.1073/pnas.1301278110 |
| format | Article |
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The Mll -dependent transcriptional network extends well beyond the previously appreciated Hox targets, is comprised of many characterized regulators of self-renewal, and contains target genes that are both dependent and independent of the MLL cofactor, Menin. Interestingly, PR-domain containing 16 emerged as a target gene that is uniquely effective at partially rescuing Mll -deficient hematopoietic stem and progenitor cells. This work highlights the tissue-specific nature of regulatory networks under the control of MLL/Trithorax family members and provides insight into the distinctions between the participation of MLL in normal hematopoiesis and in leukemia.</description><identifier>ISSN: 0027-8424</identifier><identifier>EISSN: 1091-6490</identifier><identifier>DOI: 10.1073/pnas.1301278110</identifier><identifier>PMID: 23744037</identifier><language>eng</language><publisher>United States: National Academy of Sciences</publisher><subject>Biological Sciences ; Chromatin ; Chromatin Immunoprecipitation ; Epigenesis, Genetic - physiology ; Fetal stem cells ; Gene expression ; Gene expression regulation ; Gene Regulatory Networks - physiology ; Genes ; Hematopoiesis ; Hematopoiesis - physiology ; Hematopoietic stem cells ; Hematopoietic Stem Cells - physiology ; Histone-Lysine N-Methyltransferase ; Histones ; homeotic genes ; Humans ; Leukemia ; methyltransferases ; Models, Biological ; Myeloid-Lymphoid Leukemia Protein - physiology ; neoplasm cells ; oncogene proteins ; precipitin tests ; Proto-Oncogene Proteins - physiology ; Regulator genes ; Retroviridae ; Stem cells ; transcription (genetics)</subject><ispartof>Proceedings of the National Academy of Sciences - PNAS, 2013-07, Vol.110 (29), p.12000-12005</ispartof><rights>copyright © 1993-2008 National Academy of Sciences of the United States of America</rights><rights>Copyright National Academy of Sciences Jul 16, 2013</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c591t-54a5e908e8d8c661cea0fb8a7c7a2c1d5ee29c0c1faf145c4308448e77fd26233</citedby><cites>FETCH-LOGICAL-c591t-54a5e908e8d8c661cea0fb8a7c7a2c1d5ee29c0c1faf145c4308448e77fd26233</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Uhttp://www.pnas.org/content/110/29.cover.gif</thumbnail><linktopdf>$$Uhttps://www.jstor.org/stable/pdf/42712516$$EPDF$$P50$$Gjstor$$H</linktopdf><linktohtml>$$Uhttps://www.jstor.org/stable/42712516$$EHTML$$P50$$Gjstor$$H</linktohtml><link.rule.ids>230,314,723,776,780,799,881,27901,27902,53766,53768,57992,58225</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/23744037$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Artinger, Erika L.</creatorcontrib><creatorcontrib>Mishra, Bibhu P.</creatorcontrib><creatorcontrib>Zaffuto, Kristin M.</creatorcontrib><creatorcontrib>Li, Bin E.</creatorcontrib><creatorcontrib>Chung, Elaine K. Y.</creatorcontrib><creatorcontrib>Moore, Adrian W.</creatorcontrib><creatorcontrib>Chen, Yufei</creatorcontrib><creatorcontrib>Cheng, Chao</creatorcontrib><creatorcontrib>Ernst, Patricia</creatorcontrib><title>MLL-dependent network sustains hematopoiesis</title><title>Proceedings of the National Academy of Sciences - PNAS</title><addtitle>Proc Natl Acad Sci U S A</addtitle><description>The histone methyltransferase Mixed Lineage Leukemia (MLL) is essential to maintain hematopoietic stem cells and is a leukemia protooncogene. Although clustered homeobox genes are well-characterized targets of MLL and MLL fusion oncoproteins, the range of Mll -regulated genes in normal hematopoietic cells remains unknown. Here, we identify and characterize part of the Mll -dependent transcriptional network in hematopoietic stem cells with an integrated approach by using conditional loss-of-function models, genomewide expression analyses, chromatin immunoprecipitation, and functional rescue assays. The Mll -dependent transcriptional network extends well beyond the previously appreciated Hox targets, is comprised of many characterized regulators of self-renewal, and contains target genes that are both dependent and independent of the MLL cofactor, Menin. Interestingly, PR-domain containing 16 emerged as a target gene that is uniquely effective at partially rescuing Mll -deficient hematopoietic stem and progenitor cells. 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Here, we identify and characterize part of the Mll -dependent transcriptional network in hematopoietic stem cells with an integrated approach by using conditional loss-of-function models, genomewide expression analyses, chromatin immunoprecipitation, and functional rescue assays. The Mll -dependent transcriptional network extends well beyond the previously appreciated Hox targets, is comprised of many characterized regulators of self-renewal, and contains target genes that are both dependent and independent of the MLL cofactor, Menin. Interestingly, PR-domain containing 16 emerged as a target gene that is uniquely effective at partially rescuing Mll -deficient hematopoietic stem and progenitor cells. 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| subjects | Biological Sciences Chromatin Chromatin Immunoprecipitation Epigenesis, Genetic - physiology Fetal stem cells Gene expression Gene expression regulation Gene Regulatory Networks - physiology Genes Hematopoiesis Hematopoiesis - physiology Hematopoietic stem cells Hematopoietic Stem Cells - physiology Histone-Lysine N-Methyltransferase Histones homeotic genes Humans Leukemia methyltransferases Models, Biological Myeloid-Lymphoid Leukemia Protein - physiology neoplasm cells oncogene proteins precipitin tests Proto-Oncogene Proteins - physiology Regulator genes Retroviridae Stem cells transcription (genetics) |
| title | MLL-dependent network sustains hematopoiesis |
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