Joint Binding of OTX2 and MYC in Promotor Regions Is Associated with High Gene Expression in Medulloblastoma

Both OTX2 and MYC are important oncogenes in medulloblastoma, the most common malignant brain tumor in childhood. Much is known about MYC binding to promoter regions, but OTX2 binding is hardly investigated. We used ChIP-on-chip data to analyze the binding patterns of both transcription factors in D425 medulloblastoma cells. When combining the data for all promoter regions in the genome, OTX2 binding showed a remarkable bi-modal distribution pattern with peaks around −250 bp upstream and +650 bp downstream of the transcription start sites (TSSs). Indeed, 40.2% of all OTX2-bound TSSs had more than one significant OTX2-binding peak. This OTX2-binding pattern was very different from the TSS-centered single peak binding pattern observed for MYC and other known transcription factors. However, in individual promoter regions, OTX2 and MYC have a strong tendency to bind in proximity of each other. OTX2-binding sequences are depleted near TSSs in the genome, providing an explanation for the observed bi-modal distribution of OTX2 binding. This contrasts to the enrichment of E-box sequences at TSSs. Both OTX2 and MYC binding independently correlated with higher gene expression. Interestingly, genes of promoter regions with multiple OTX2 binding as well as MYC binding showed the highest expression levels in D425 cells and in primary medulloblastomas. Genes within this class of promoter regions were enriched for medulloblastoma and stem cell specific genes. Our data suggest an important functional interaction between OTX2 and MYC in regulating gene expression in medulloblastoma

The Confrontation between General Relativity and Experiment

The status of experimental tests of general relativity and of theoretical frameworks for analysing them is reviewed. Einstein's equivalence principle (EEP) is well supported by experiments such as the Eotvos experiment, tests of special relativity, and the gravitational redshift experiment. Future tests of EEP and of the inverse square law are searching for new interactions arising from unification or quantum gravity. Tests of general relativity at the post-Newtonian level have reached high precision, including the light deflection, the Shapiro time delay, the perihelion advance of Mercury, and the Nordtvedt effect in lunar motion. Gravitational-wave damping has been detected in an amount that agrees with general relativity to better than half a percent using the Hulse-Taylor binary pulsar, and other binary pulsar systems have yielded other tests, especially of strong-field effects. When direct observation of gravitational radiation from astrophysical sources begins, new tests of general relativity will be possible.Comment: 89 pages, 8 figures; an update of the Living Review article originally published in 2001; final published version incorporating referees' suggestion