Like computers, our cells depend on operating systems to drive normal functions. The gene expression programs are the source code our cells rely on to play theirbiological functions. Corrupted programs trigger diseases. This research proposaluses embryonic stem cells to study how cellular operating systems are regulated. We recently discovered that SMC complexes connect the chromosome architecturewith regulation of the gene expression program. SMC complexes subunits aremutated in cancers and developmental syndromes including the Cornelia de LangeSyndrome (CdLS), an autosomal dominant syndrome. Defining how the cellular operating system is regulated is crucial to understanding defective gene expressionprograms in diseases such as CdLS.