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Integrated genome-wide chromatin occupancy and expression analyses identify key myeloid pro-differentiation transcription factors repressed by Myb.

Zhao L, Glazov EA, Pattabiraman DR, Al-Owaidi F, Zhang P, Brown MA, Leo PJ, Gonda TJ - Nucleic Acids Res. (2011)

Bottom Line: Importantly, we also show that, despite being usually considered as a transactivator, Myb also functions to repress approximately half of its direct targets, including several key regulators of myeloid differentiation, such as Sfpi1 (also known as Pu.1), Runx1, Junb and Cebpb.Furthermore, our results demonstrate that interaction with p300, an established coactivator for Myb, is unexpectedly required for Myb-mediated transcriptional repression.We propose that the repression of the above mentioned key pro-differentiation factors may contribute essentially to Myb's ability to suppress differentiation and promote self-renewal, thus maintaining progenitor cells in an undifferentiated state and promoting leukemic transformation.

View Article: PubMed Central - PubMed

Affiliation: The University of Queensland Diamantina Institute, Brisbane, Queensland 4102, Australia.

ABSTRACT
To gain insight into the mechanisms by which the Myb transcription factor controls normal hematopoiesis and particularly, how it contributes to leukemogenesis, we mapped the genome-wide occupancy of Myb by chromatin immunoprecipitation followed by massively parallel sequencing (ChIP-Seq) in ERMYB myeloid progenitor cells. By integrating the genome occupancy data with whole genome expression profiling data, we identified a Myb-regulated transcriptional program. Gene signatures for leukemia stem cells, normal hematopoietic stem/progenitor cells and myeloid development were overrepresented in 2368 Myb regulated genes. Of these, Myb bound directly near or within 793 genes. Myb directly activates some genes known critical in maintaining hematopoietic stem cells, such as Gfi1 and Cited2. Importantly, we also show that, despite being usually considered as a transactivator, Myb also functions to repress approximately half of its direct targets, including several key regulators of myeloid differentiation, such as Sfpi1 (also known as Pu.1), Runx1, Junb and Cebpb. Furthermore, our results demonstrate that interaction with p300, an established coactivator for Myb, is unexpectedly required for Myb-mediated transcriptional repression. We propose that the repression of the above mentioned key pro-differentiation factors may contribute essentially to Myb's ability to suppress differentiation and promote self-renewal, thus maintaining progenitor cells in an undifferentiated state and promoting leukemic transformation.

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MBRs were enriched near Myb target genes. (A) Direct Myb targets (classes A and B) generally have significantly more MBRs than those Myb bound but not regulated or not expressed genes (class C). *P < 0.05 (Wilcoxon rank sum test). (B) MBRs are enriched in the proximity of TSS of Myb activated genes (classes A and B). Myb repressed genes appeared to have more MBRs at locations relatively distal to TSS. Average numbers of MBR per gene of each microarray class were plotted against their distances relative to the nearest TSS in 1 kb bins up to 20 kb away from TSS.
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Figure 5: MBRs were enriched near Myb target genes. (A) Direct Myb targets (classes A and B) generally have significantly more MBRs than those Myb bound but not regulated or not expressed genes (class C). *P < 0.05 (Wilcoxon rank sum test). (B) MBRs are enriched in the proximity of TSS of Myb activated genes (classes A and B). Myb repressed genes appeared to have more MBRs at locations relatively distal to TSS. Average numbers of MBR per gene of each microarray class were plotted against their distances relative to the nearest TSS in 1 kb bins up to 20 kb away from TSS.

Mentions: The majority of Myb bound genes (80.7%; Figure 4A) were not clearly regulated by Myb. In order to gain insights into why some Myb bound genes were regulated by Myb whereas others not, we compared the average number of associated MBRs per gene for Myb bound genes in different microarray classes (Figure 5A). Direct Myb targets (bound genes in classes A and B) appeared to have significantly more MBRs than those bound but not Myb-regulated or not expressed (class C), with the highest enrichment seen for Myb bound and activated genes in class A. Consistently, distribution analysis of MBRs relative to genes in each microarray class revealed higher enrichment of MBRs near TSS of Myb activated genes (classes A and B) compared with genes not regulated or expressed (class C) whereas Myb repressed genes (classes A and B) appear to have more MBRs at locations further to TSS (Figure 5B).Figure 5.


Integrated genome-wide chromatin occupancy and expression analyses identify key myeloid pro-differentiation transcription factors repressed by Myb.

Zhao L, Glazov EA, Pattabiraman DR, Al-Owaidi F, Zhang P, Brown MA, Leo PJ, Gonda TJ - Nucleic Acids Res. (2011)

MBRs were enriched near Myb target genes. (A) Direct Myb targets (classes A and B) generally have significantly more MBRs than those Myb bound but not regulated or not expressed genes (class C). *P < 0.05 (Wilcoxon rank sum test). (B) MBRs are enriched in the proximity of TSS of Myb activated genes (classes A and B). Myb repressed genes appeared to have more MBRs at locations relatively distal to TSS. Average numbers of MBR per gene of each microarray class were plotted against their distances relative to the nearest TSS in 1 kb bins up to 20 kb away from TSS.
© Copyright Policy - creative-commons
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC3113568&req=5

Figure 5: MBRs were enriched near Myb target genes. (A) Direct Myb targets (classes A and B) generally have significantly more MBRs than those Myb bound but not regulated or not expressed genes (class C). *P < 0.05 (Wilcoxon rank sum test). (B) MBRs are enriched in the proximity of TSS of Myb activated genes (classes A and B). Myb repressed genes appeared to have more MBRs at locations relatively distal to TSS. Average numbers of MBR per gene of each microarray class were plotted against their distances relative to the nearest TSS in 1 kb bins up to 20 kb away from TSS.
Mentions: The majority of Myb bound genes (80.7%; Figure 4A) were not clearly regulated by Myb. In order to gain insights into why some Myb bound genes were regulated by Myb whereas others not, we compared the average number of associated MBRs per gene for Myb bound genes in different microarray classes (Figure 5A). Direct Myb targets (bound genes in classes A and B) appeared to have significantly more MBRs than those bound but not Myb-regulated or not expressed (class C), with the highest enrichment seen for Myb bound and activated genes in class A. Consistently, distribution analysis of MBRs relative to genes in each microarray class revealed higher enrichment of MBRs near TSS of Myb activated genes (classes A and B) compared with genes not regulated or expressed (class C) whereas Myb repressed genes (classes A and B) appear to have more MBRs at locations further to TSS (Figure 5B).Figure 5.

Bottom Line: Importantly, we also show that, despite being usually considered as a transactivator, Myb also functions to repress approximately half of its direct targets, including several key regulators of myeloid differentiation, such as Sfpi1 (also known as Pu.1), Runx1, Junb and Cebpb.Furthermore, our results demonstrate that interaction with p300, an established coactivator for Myb, is unexpectedly required for Myb-mediated transcriptional repression.We propose that the repression of the above mentioned key pro-differentiation factors may contribute essentially to Myb's ability to suppress differentiation and promote self-renewal, thus maintaining progenitor cells in an undifferentiated state and promoting leukemic transformation.

View Article: PubMed Central - PubMed

Affiliation: The University of Queensland Diamantina Institute, Brisbane, Queensland 4102, Australia.

ABSTRACT
To gain insight into the mechanisms by which the Myb transcription factor controls normal hematopoiesis and particularly, how it contributes to leukemogenesis, we mapped the genome-wide occupancy of Myb by chromatin immunoprecipitation followed by massively parallel sequencing (ChIP-Seq) in ERMYB myeloid progenitor cells. By integrating the genome occupancy data with whole genome expression profiling data, we identified a Myb-regulated transcriptional program. Gene signatures for leukemia stem cells, normal hematopoietic stem/progenitor cells and myeloid development were overrepresented in 2368 Myb regulated genes. Of these, Myb bound directly near or within 793 genes. Myb directly activates some genes known critical in maintaining hematopoietic stem cells, such as Gfi1 and Cited2. Importantly, we also show that, despite being usually considered as a transactivator, Myb also functions to repress approximately half of its direct targets, including several key regulators of myeloid differentiation, such as Sfpi1 (also known as Pu.1), Runx1, Junb and Cebpb. Furthermore, our results demonstrate that interaction with p300, an established coactivator for Myb, is unexpectedly required for Myb-mediated transcriptional repression. We propose that the repression of the above mentioned key pro-differentiation factors may contribute essentially to Myb's ability to suppress differentiation and promote self-renewal, thus maintaining progenitor cells in an undifferentiated state and promoting leukemic transformation.

Show MeSH
Related in: MedlinePlus