Grant: Maud Menten New Principal Investigator Prize - Biomedical

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 their biological functions. Corrupted programs can trigger disease. Embryonic stem cells (ESCs) are under scrutiny for their potential in regenerative medicine and represent a great model system to study rules controlling the gene expression program. Factors regulating gene expression programs are often mutated in human diseases and ESCs are a unique model-system to study these transcription-related disease mechanisms. Cellular operating systems require a web of connections to deliver an accurate gene expression program. Each individual gene can be access following a precise number of commands that need to be executed in an orderly fashion. From the last 30 years of research, multiple regulators emerged to control the cell-type specific gene expression program including transcription factors, chromatin regulators and other co-factors. These factors influence the immediate environment surrounding a gene. Using ESCs, we recently discovered a secondary architecture across the genome established by SMC complexes, a protein family conserved through evolution. SMC complexes connect the regulation of the gene expression program with the chromosome architecture opening a new folder of possibilities to regulate genes. Subunits of SMC complexes are often mutated in cancer and developmental syndrome including the Cornelia de Lange syndrome (CdLS). CdLS is an autosomal dominant syndrome affecting 1 per 10,000 live births and typically characterized by a wide array of developmental defects. Defining how the cellular operating system is regulated is crucial to get one step closer to understanding defective gene expression programs in diseases such as CdLS. Furthermore, this research could open new treatment avenues for other diseases caused by transcription-related events.