Purine-rich box1 (PU.1) is a transcription factor that not only has a key role in the development of most hematopoietic cell lineages but also in the suppression of leukemia. To exert these functions, PU.1 can cross-talk with multiple different proteins by forming complexes in order to activate or repress transcription. Among its protein partners are chromatin remodelers, DNA methyltransferases, and a number of other transcription factors with important roles in hematopoiesis. While a great deal of knowledge has been acquired about PU.1 function over the years, it was the development of novel genome-wide technologies, which boosted our understanding of how PU.1 acts on the chromatin to drive its repertoire of target genes. This review summarizes current knowledge and ideas of molecular mechanisms by which PU.1 controls hematopoiesis and suppresses leukemia.
RUNX1 is known to be an essential transcription factor for generating hematopoietic stem cells (HSC), but much less is known about its role in the downstream process of hematopoietic differentiation. RUNX1 has been shown to be part of a large transcription factor complex, together with LDB1, GATA1, TAL1, and ETO2 (N. Meier et al., Development 133 :4913–4923, 2006) in erythroid cells. We used a tagging strategy to show that RUNX1 interacts with two novel protein partners, LSD1 and MYEF2, in erythroid cells. MYEF2 is bound in undifferentiated cells and is lost upon differentiation, whereas LSD1 is bound in differentiated cells. Chromatin immunoprecipitation followed by sequencing (ChIP-seq) and microarray expression analysis were used to show that RUNX1 binds approximately 9,000 target sites in erythroid cells and is primarily active in the undifferentiated state. Functional analysis shows that a subset of the target genes is suppressed by RUNX1 via the newly identified partner MYEF2. Knockdown of Myef2 expression in developing zebrafish results in a reduced number of HSC.
SUMMARYDietary oils (such as borage oil), which are rich in g-linolenic acid (GLA), have been shown to be bene®cial under in¯ammatory conditions. Dihomo-GLA (DGLA) is synthesized directly from GLA and forms a substrate for cyclooxygenase (COX) enzymes, resulting in the synthesis of lipid mediators (eicosanoids). In the present study, the immunomodulatory effects of DGLA were investigated and compared with those of other relevant fatty acids. Freshly isolated human peripheral blood mononuclear cells (PBMC) were cultured in fatty acid (100 mM)-enriched medium for 48 hr. Subsequently, cells were stimulated with lipopolysaccharide (LPS) for 20 hr and the cytokine levels were measured, in supernatants, by enzyme-linked immunosorbent assay (ELISA). Phospholipids were analysed by gas chromatography. Fatty acids were readily taken up, metabolized and incorporated into cellular phospholipids. Compared with the other fatty acids tested, DGLA exerted pronounced modulatory effects on cytokine production. Tumour necrosis factor-a (TNF-a) and interleukin (IL)-10 levels were reduced to 60% of control levels, whereas IL-6 levels were not affected by DGLA. Kinetic studies showed that peak levels of TNF-a, occurring early after LPS addition, were inhibited strongly, whereas IL-10 levels were not affected until 15 hr after stimulation. Both the reduction of cytokine levels and the decrease in arachidonic acid levels in these cells, induced by DGLA, were dose dependent, suggesting a shift in eicosanoidsubtype synthesis. However, although some DGLA-derived eicosanoids similarly reduced TNF-a levels, the effects of DGLA were probably not mediated by COX products, as the addition of indomethacin did not alter the effects of DGLA. In conclusion, these results suggest that DGLA affects cytokine production by human PBMC independently of COX activation.
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