Studies

The Gilbert Group

The focus of the Gilbert research group is to understand how human chromosomes are organized within the nucleus to carry out their functions. Their research program is built on the understanding that all cells replicate their DNA in a temporal sequence that is specific to each cell type and is disrupted in all diseases studied to date. However, both the mechanisms of this “replication timing” program and its biological significance remain a mystery.

Faithfully duplicating our DNA is arguably the most fundamental thing that our cells do, and mistakes in this process are major drivers of disease, yet we understand very little about its regulation. Replication timing is clearly related to the 3-dimensional organization of chromosomes such that structural and functional units of chromosomes replicate coordinately, often through the synchronous firing of clusters of replication origins that encompass domains of approximately 0.5Mb. Each of these replication domains is programmed to replicate at a specific time during S-phase. In general, transcriptionally active (euchromatin) domains replicate early in S-phase and transcriptionally silent (heterochromatin) domains replicate late. The order in which these segments replicate is disrupted in many diseases, including all cancers. However, there is still no conclusive understanding of why replication takes place in the order it does, or why it is different in each of the tissues of our body.

The primary motivation for Dr. Gilbert’s research is that these units that we call “replication domains provide us with a molecular handle into the higher order structural and functional organization of chromosomes. They hypothesize that, since it is not just DNA that replicates but the entire epigenome and its 3D organization, controlling where and when replication takes place can serve as a convenient means for cells to maintain stable epigenetic states or to change those states during cell fate transitions. The work in the Gilbert laboratory can be divided into the following major areas: the developmental regulation of DNA replication, regulation of replication timing during the cell cycle, discovery of what regulates the sites where replication initiates, and human replication origins.