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PU.1 activation relieves GATA-1-mediated repression of Cebpa and Cbfb during leukemia differentiation.
| Content Provider | Semantic Scholar |
|---|---|
| Author | Burda, Pavel Čuřík, Nikola Kokavec, Juraj Bašová, Petra Mikulenková, Dana Skoultchi, Arthur Skoultchi Zavadil, Jiří Stopka, Tomás |
| Copyright Year | 2009 |
| Abstract | Hematopoietic transcription factors GATA-1 and PU.1 bind each other on DNA to block transcriptional programs of undesired lineage during hematopoietic commitment. Murine erythroleukemia (MEL) cells that coexpress GATA-1 and PU.1 are blocked at the blast stage but respond to molecular removal (downregulation) of PU.1 or addition (upregulation) of GATA-1 by inducing terminal erythroid differentiation. To test whether GATA-1 blocks PU.1 in MEL cells, we have conditionally activated a transgenic PU.1 protein fused with the estrogen receptor ligand-binding domain (PUER), resulting in activation of a myeloid transcriptional program. Gene expression arrays identified components of the PU.1-dependent transcriptome negatively regulated by GATA-1 in MEL cells, including CCAAT/enhancer binding protein alpha (Cebpa) and core-binding factor, beta subunit (Cbfb), which encode two key hematopoietic transcription factors. Inhibition of GATA-1 by small interfering RNA resulted in derepression of PU.1 target genes. Chromatin immunoprecipitation and reporter assays identified PU.1 motif sequences near Cebpa and Cbfb that are co-occupied by PU.1 and GATA-1 in the leukemic blasts. Significant derepression of Cebpa and Cbfb is achieved in MEL cells by either activation of PU.1 or knockdown of GATA-1. Furthermore, transcriptional regulation of these loci by manipulating the levels of PU.1 and GATA-1 involves quantitative increases in a transcriptionally active chromatin mark: acetylation of histone H3K9. Collectively, we show that either activation of PU.1 or inhibition of GATA-1 efficiently reverses the transcriptional block imposed by GATA-1 and leads to the activation of a myeloid transcriptional program directed by PU.1. |
| Starting Page | 2292 |
| Ending Page | 2295 |
| Page Count | 4 |
| File Format | PDF HTM / HTML |
| Alternate Webpage(s) | http://www.einstein.yu.edu/uploadedFiles/departments/cell-biology/PDF/Skoultchi/1693.full.pdf |
| PubMed reference number | 19825991v1 |
| Alternate Webpage(s) | https://doi.org/10.1158/1541-7786.MCR-09-0031 |
| DOI | 10.1158/1541-7786.mcr-09-0031 |
| Journal | Molecular cancer research : MCR |
| Volume Number | 7 |
| Issue Number | 10 |
| Language | English |
| Access Restriction | Open |
| Subject Keyword | Acute Erythroblastic Leukemia Blast Phase Cell Differentiation process Enhancer of transcription Estrogens GATA1 gene GATA1 protein, human Gene Expression Histone H3 Lysine 9 Histones Leukemic Blast Count Ligands Non-Small Cell Lung Carcinoma Protein Domain RNA Repression, Psychology SPI1 gene SPI1 wt Allele TRANSCRIPTION FACTOR Transcription, Genetic Transcriptional Regulation Transcriptome chromatin immunoprecipitation estrogen receptor alpha, human |
| Content Type | Text |
| Resource Type | Article |
