Structure and function of the NCoR complex and SETD5

The human genome contains around three billion base pairs of DNA, the molecule that stores the information that we pass on to future generations. This huge amount of information is packed into nearly every cell of the human body by wrapping it around proteins called histones, creating many small DNA-protein packages called nucleosomes. Around twenty thousand genes are contained within the human genome, and it is extremely important for normal human development that these genes are read out at the right times. Small chemical changes to histones can affect the accessibility of genes, and can change if, when, and how much these genes are read out. One machine that can cause these chemical changes is called the nuclear receptor co-repressor (NCoR) complex. It interacts with a protein called SET-domain containing 5 (SETD5). Mutations in the NCoR complex and SETD5 have been linked to intellectual disability (impairment of general mental abilities) and neurodevelopmental disorders, two conditions that affect approximately 2-5% of children worldwide. These and other data point to an essential role played by the NCoR complex and SETD5 in the context of human development. However, how exactly they work together to change how genes are read out is not yet known. In this project, we aim to learn about how the NCoR complex and SETD5 work through biochemistry and by using high- resolution electron microscopy to understand how the NCoR complex alone or together with SETD5 can interact with nucleosomes. These results will help us understand how this process works in healthy people and how the mutations cause disease, and also have the potential to provide insights useful for designing therapeutic approaches.

No additional funding sources recorded.