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Control of RUNX-induced repression of Notch signaling by MLF and its partner DnaJ-1 during Drosophila hematopoiesis

A tight regulation of transcription factor activity is critical for proper development. For instance, modifications of RUNX transcription factors dosage are associated with several diseases, including hematopoietic malignancies. In Drosophila, Myeloid Leukemia Factor (MLF) has been shown to control...

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Autores principales: Miller, Marion, Chen, Aichun, Gobert, Vanessa, Augé, Benoit, Beau, Mathilde, Burlet-Schiltz, Odile, Haenlin, Marc, Waltzer, Lucas
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5549762/
https://www.ncbi.nlm.nih.gov/pubmed/28742844
http://dx.doi.org/10.1371/journal.pgen.1006932
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author Miller, Marion
Chen, Aichun
Gobert, Vanessa
Augé, Benoit
Beau, Mathilde
Burlet-Schiltz, Odile
Haenlin, Marc
Waltzer, Lucas
author_facet Miller, Marion
Chen, Aichun
Gobert, Vanessa
Augé, Benoit
Beau, Mathilde
Burlet-Schiltz, Odile
Haenlin, Marc
Waltzer, Lucas
author_sort Miller, Marion
collection PubMed
description A tight regulation of transcription factor activity is critical for proper development. For instance, modifications of RUNX transcription factors dosage are associated with several diseases, including hematopoietic malignancies. In Drosophila, Myeloid Leukemia Factor (MLF) has been shown to control blood cell development by stabilizing the RUNX transcription factor Lozenge (Lz). However, the mechanism of action of this conserved family of proteins involved in leukemia remains largely unknown. Here we further characterized MLF’s mode of action in Drosophila blood cells using proteomic, transcriptomic and genetic approaches. Our results show that MLF and the Hsp40 co-chaperone family member DnaJ-1 interact through conserved domains and we demonstrate that both proteins bind and stabilize Lz in cell culture, suggesting that MLF and DnaJ-1 form a chaperone complex that directly regulates Lz activity. Importantly, dnaj-1 loss causes an increase in Lz(+) blood cell number and size similarly as in mlf mutant larvae. Moreover we find that dnaj-1 genetically interacts with mlf to control Lz level and Lz(+) blood cell development in vivo. In addition, we show that mlf and dnaj-1 loss alters Lz(+) cell differentiation and that the increase in Lz(+) blood cell number and size observed in these mutants is caused by an overactivation of the Notch signaling pathway. Finally, using different conditions to manipulate Lz activity, we show that high levels of Lz are required to repress Notch transcription and signaling. All together, our data indicate that the MLF/DnaJ-1-dependent increase in Lz level allows the repression of Notch expression and signaling to prevent aberrant blood cell development. Thus our findings establish a functional link between MLF and the co-chaperone DnaJ-1 to control RUNX transcription factor activity and Notch signaling during blood cell development in vivo.
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spelling pubmed-55497622017-08-12 Control of RUNX-induced repression of Notch signaling by MLF and its partner DnaJ-1 during Drosophila hematopoiesis Miller, Marion Chen, Aichun Gobert, Vanessa Augé, Benoit Beau, Mathilde Burlet-Schiltz, Odile Haenlin, Marc Waltzer, Lucas PLoS Genet Research Article A tight regulation of transcription factor activity is critical for proper development. For instance, modifications of RUNX transcription factors dosage are associated with several diseases, including hematopoietic malignancies. In Drosophila, Myeloid Leukemia Factor (MLF) has been shown to control blood cell development by stabilizing the RUNX transcription factor Lozenge (Lz). However, the mechanism of action of this conserved family of proteins involved in leukemia remains largely unknown. Here we further characterized MLF’s mode of action in Drosophila blood cells using proteomic, transcriptomic and genetic approaches. Our results show that MLF and the Hsp40 co-chaperone family member DnaJ-1 interact through conserved domains and we demonstrate that both proteins bind and stabilize Lz in cell culture, suggesting that MLF and DnaJ-1 form a chaperone complex that directly regulates Lz activity. Importantly, dnaj-1 loss causes an increase in Lz(+) blood cell number and size similarly as in mlf mutant larvae. Moreover we find that dnaj-1 genetically interacts with mlf to control Lz level and Lz(+) blood cell development in vivo. In addition, we show that mlf and dnaj-1 loss alters Lz(+) cell differentiation and that the increase in Lz(+) blood cell number and size observed in these mutants is caused by an overactivation of the Notch signaling pathway. Finally, using different conditions to manipulate Lz activity, we show that high levels of Lz are required to repress Notch transcription and signaling. All together, our data indicate that the MLF/DnaJ-1-dependent increase in Lz level allows the repression of Notch expression and signaling to prevent aberrant blood cell development. Thus our findings establish a functional link between MLF and the co-chaperone DnaJ-1 to control RUNX transcription factor activity and Notch signaling during blood cell development in vivo. Public Library of Science 2017-07-25 /pmc/articles/PMC5549762/ /pubmed/28742844 http://dx.doi.org/10.1371/journal.pgen.1006932 Text en © 2017 Miller et al http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Miller, Marion
Chen, Aichun
Gobert, Vanessa
Augé, Benoit
Beau, Mathilde
Burlet-Schiltz, Odile
Haenlin, Marc
Waltzer, Lucas
Control of RUNX-induced repression of Notch signaling by MLF and its partner DnaJ-1 during Drosophila hematopoiesis
title Control of RUNX-induced repression of Notch signaling by MLF and its partner DnaJ-1 during Drosophila hematopoiesis
title_full Control of RUNX-induced repression of Notch signaling by MLF and its partner DnaJ-1 during Drosophila hematopoiesis
title_fullStr Control of RUNX-induced repression of Notch signaling by MLF and its partner DnaJ-1 during Drosophila hematopoiesis
title_full_unstemmed Control of RUNX-induced repression of Notch signaling by MLF and its partner DnaJ-1 during Drosophila hematopoiesis
title_short Control of RUNX-induced repression of Notch signaling by MLF and its partner DnaJ-1 during Drosophila hematopoiesis
title_sort control of runx-induced repression of notch signaling by mlf and its partner dnaj-1 during drosophila hematopoiesis
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5549762/
https://www.ncbi.nlm.nih.gov/pubmed/28742844
http://dx.doi.org/10.1371/journal.pgen.1006932
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