Leukemogenic MLL-ENL Fusions Induce Alternative Chromatin States to Drive a Functionally Dichotomous Group of Target Genes
MLL fusions are leukemogenic transcription factors that enhance transcriptional elongation through modification of chromatin and RNA Pol II. Global transcription rates and chromatin changes accompanying the transformation process induced by MLL-ENL were monitored by nascent RNA-seq and ChIP-seq, rev...
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doaj-cabe070e4af9489996ee8a2cc666ea6a2020-11-25T01:51:03ZengElsevierCell Reports2211-12472016-04-0115231032210.1016/j.celrep.2016.03.018Leukemogenic MLL-ENL Fusions Induce Alternative Chromatin States to Drive a Functionally Dichotomous Group of Target GenesMaria-Paz Garcia-Cuellar0Christian Büttner1Christoph Bartenhagen2Martin Dugas3Robert K. Slany4Department of Genetics, Friedrich-Alexander-University Erlangen-Nürnberg, 91058 Erlangen, GermanyInstitute of Human Genetics, Friedrich-Alexander-University Erlangen-Nürnberg, 91058 Erlangen, GermanyDepartment of Medical Informatics, University Münster, 48149 Münster, GermanyDepartment of Medical Informatics, University Münster, 48149 Münster, GermanyDepartment of Genetics, Friedrich-Alexander-University Erlangen-Nürnberg, 91058 Erlangen, GermanyMLL fusions are leukemogenic transcription factors that enhance transcriptional elongation through modification of chromatin and RNA Pol II. Global transcription rates and chromatin changes accompanying the transformation process induced by MLL-ENL were monitored by nascent RNA-seq and ChIP-seq, revealing 165 direct target genes separated into two distinct clades. ME5 genes bound MLL-ENL at the promoter, relied on DOT1L-mediated histone methylation, and coded preferentially for transcription factors, including many homeobox genes. A distinct ME3 group accumulated MLL-ENL beyond the termination site, was dependent on P-TEFb-mediated phosphorylation of RNA Pol II for transcription, and translated mainly into proteins involved in RNA biology and ribosome assembly. This dichotomy was reflected by a differential sensitivity toward small molecule inhibitors, suggesting the possibility of a combinatorial strategy for treatment of MLL-induced leukemia.http://www.sciencedirect.com/science/article/pii/S2211124716302595leukemiachromatinMLL-ENLP-TEFbDOT1Linhibitors |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Maria-Paz Garcia-Cuellar Christian Büttner Christoph Bartenhagen Martin Dugas Robert K. Slany |
spellingShingle |
Maria-Paz Garcia-Cuellar Christian Büttner Christoph Bartenhagen Martin Dugas Robert K. Slany Leukemogenic MLL-ENL Fusions Induce Alternative Chromatin States to Drive a Functionally Dichotomous Group of Target Genes Cell Reports leukemia chromatin MLL-ENL P-TEFb DOT1L inhibitors |
author_facet |
Maria-Paz Garcia-Cuellar Christian Büttner Christoph Bartenhagen Martin Dugas Robert K. Slany |
author_sort |
Maria-Paz Garcia-Cuellar |
title |
Leukemogenic MLL-ENL Fusions Induce Alternative Chromatin States to Drive a Functionally Dichotomous Group of Target Genes |
title_short |
Leukemogenic MLL-ENL Fusions Induce Alternative Chromatin States to Drive a Functionally Dichotomous Group of Target Genes |
title_full |
Leukemogenic MLL-ENL Fusions Induce Alternative Chromatin States to Drive a Functionally Dichotomous Group of Target Genes |
title_fullStr |
Leukemogenic MLL-ENL Fusions Induce Alternative Chromatin States to Drive a Functionally Dichotomous Group of Target Genes |
title_full_unstemmed |
Leukemogenic MLL-ENL Fusions Induce Alternative Chromatin States to Drive a Functionally Dichotomous Group of Target Genes |
title_sort |
leukemogenic mll-enl fusions induce alternative chromatin states to drive a functionally dichotomous group of target genes |
publisher |
Elsevier |
series |
Cell Reports |
issn |
2211-1247 |
publishDate |
2016-04-01 |
description |
MLL fusions are leukemogenic transcription factors that enhance transcriptional elongation through modification of chromatin and RNA Pol II. Global transcription rates and chromatin changes accompanying the transformation process induced by MLL-ENL were monitored by nascent RNA-seq and ChIP-seq, revealing 165 direct target genes separated into two distinct clades. ME5 genes bound MLL-ENL at the promoter, relied on DOT1L-mediated histone methylation, and coded preferentially for transcription factors, including many homeobox genes. A distinct ME3 group accumulated MLL-ENL beyond the termination site, was dependent on P-TEFb-mediated phosphorylation of RNA Pol II for transcription, and translated mainly into proteins involved in RNA biology and ribosome assembly. This dichotomy was reflected by a differential sensitivity toward small molecule inhibitors, suggesting the possibility of a combinatorial strategy for treatment of MLL-induced leukemia. |
topic |
leukemia chromatin MLL-ENL P-TEFb DOT1L inhibitors |
url |
http://www.sciencedirect.com/science/article/pii/S2211124716302595 |
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