Roles of the sister chromatid cohesion apparatus in gene expression and development

The goals of our studies are to understand how components of the sister chromatid cohesin apparatus regulate gene expression and development. The Nipped‐B protein of Drosophila facilitates expression of the cut and Ubx homeobox genes, and is required for sister chromatid cohesion because it loads the cohesin complex onto chromosomes. Heterozygous loss‐of‐function Nipped‐B mutations reduce cut and Ubx expression without causing defects in sister chromatid cohesion, while homozygous Nipped‐B mutations are lethal and cause severe cohesion defects. We find that partial reduction of cohesin subunit levels by RNAi or mutation increases expression of cut , which is opposite to the effect of reducing Nipped‐B, without causing cohesion defects. A unique mutation in the pds5 cohesion factor gene that decreases binding of cohesin to chromosomes when homozygous, dominantly increases cut expression without causing cohesion defects. We find that cohesin binds to multiple sites the cut gene regulatory region in cultured Drosophila cell lines. We postulate that cohesin inhibits cut gene expression, perhaps by blocking enhancer‐promoter interactions. We also hypothesize that Nipped‐B facilitates cut activation by removing or relocating cohesin. Loss‐of function mutations in the human homolog of Nipped‐B , NIPBL , cause Cornelia de Lange syndrome (CdLS), a severe developmental disorder that causes slow growth, mental retardation and defects in multiple limbs and organs. We propose that the CdLS developmental deficits are caused by changes in gene expression similar to those we see in Drosophila, and that defects in cohesion are unlikely to play a significant role.