Figure 4

Model for diverse cohesinopathy phenotypes. In interphase (red shading), cohesin binding to chromatin is dynamic, with varying residency times. Interphase cohesin binding is likely to be cell type-specific and to contribute toward regulating developmental genes. Mutations in cohesin subunits and their key interphase regulators (e.g., Nipbl, Hdac8) primarily impact on the regulation of gene expression, including transcriptional regulation of growth pathways. This results in syndromic developmental defects that derive from dysregulated transcription, with the possibility of cell death as a contributing factor. From S phase to G2/M (blue shading), the overriding function of cohesin involves sister chromatid cohesion and DNA damage repair. Key regulators in this process include the CoAT ESCO2 and other DNA damage repair proteins. Mutations in these regulators result in chromosome segregation defects, genomic instability, and cell death. Increased cell death and reduced cell proliferation results in too few cells to make up body structures, leading to a different class of developmental defects and dysregulation of metabolic pathways. Transcription of a small subset of hypersensitive genes, including some in the Notch signaling pathway, appears to be sensitive to both interphase and S/G2 modes of cohesin binding.