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.