Our overarching goal is to understand how cells establish and maintain identity. We are particularly interested in how cardiac cell types are specified, and the implications of this process for congenital heart disease and congestive heart failure. We leverage classic models of stem cell biology and readily work across disciplines to dissect the underpinnings of how genome organization shapes cell identity and fate. We work on this because it is not well understood how entire gene programs are coordinately enacted, such as those that happen as a cell progressively restricts. In addition, the promise of cell-based regenerative therapies requires efficient generation of cells and tissues. We hope our studies will help add to the foundation for these efforts.
The higher-order mechanisms that control cell fate are relatively poorly understood. It has become apparent that the genome is folded and organized in a stereotypical manner in three-dimensional space. We are interested in understanding how the organization of the genome in 3D space establishes and maintains cell identity. Analogous to a storage space, in which items must be organized to maximize access, we hypothesize that organization in the nucleus follows the same logic. Genomic material which is accessed the least is at the nuclear periphery (the back of the storage space). Areas of the genome containing genes that are or need to be actively transcribed are organized in the nucleoplasm (the front of the storage space). My laboratory focuses on the central hypothesis that dynamic spatial distribution of the genome in the nucleus is determinant of cell fate and that decoding the rules that instruct nuclear lamina-chromatin interactions will inform how this is achieved. We are interested in:
- Discovery: Comprehensively defining peripheral chromatin domains across human lineages.
- Mechanism: Deciphering how spatial distribution of chromatin shapes cell fate.
- Disease: Determining how nuclear architecture drives laminopathy phenotypes.
We routinely work across disciplines and use a combination of single-cell, next generation sequencing, live imaging, and proteomic approaches in the laboratory.
Establishing Cell Identity
A second, complementary, focus in the laboratory is defining how cell identity is established after mitosis. After each round of mitosis, gene programs must be precisely re-established in order to preserve cell identity. However, the underpinnings of how this occurs, especially during cardiac development are not well understood. We are trying to define the factors and mechanisms responsible for establishing cell identity after cardiac cells divide.