Positive regulation of c- Myc by cohesin is direct, and evolutionarily conserved

Contact between sister chromatids from S phase to anaphase depends on cohesin, a large multi-subunit protein complex. Mutations in sister chromatid cohesion proteins underlie the human developmental condition, Cornelia de Lange syndrome. Roles for cohesin in regulating gene expression, sometimes in combination with CCCTC-binding factor (CTCF), have emerged. We analyzed zebrafish embryos null for cohesin subunit rad21 using microarrays to determine global effects of cohesin on gene expression during embryogenesis. This identified Rad21-associated gene networks that included myca (zebrafish c- myc), p53 and mdm2. In zebrafish, cohesin binds to the transcription start sites of p53 and mdm2, and depletion of either Rad21 or CTCF increased their transcription. In contrast, myca expression was strongly downregulated upon loss of Rad21 while depletion of CTCF had little effect. Depletion of Rad21 or the cohesin-loading factor Nipped-B in Drosophila cells also reduced expression of myc and Myc target genes. Cohesin bound the transcription start site plus an upstream predicted CTCF binding site at zebrafish myca. Binding and positive regulation of the c- Myc gene by cohesin is conserved through evolution, indicating that this regulation is likely to be direct. The exact mechanism of regulation is unknown, but local changes in histone modification associated with transcription repression at the myca gene were observed in rad21 mutants.