Lab mission:
The mission of the McCarthy lab is to understand how epigenetic gene repression regulates cell identity and function, and to utilize this knowledge to control cell identity for generating cell therapeutics and treat disease.
Project 1:
Disrupting heterochromatin to enhance reprogramming of fibroblasts to hepatocyte like cells for liver cell therapy and transplantation
Liver transplantation is the only curative treatment for most liver diseases, but the supply of donor liver tissue is not enough to meet the demand. Additionally, the need for lifetime immunosuppressant treatment to avoid rejection is especially problematic in the pediatric population. H3K9me3 heterochromatin has been shown to be the primary barrier to gene activation during reprogramming to multiple lineages including to hepatocyte-like cells (Becker, McCarthy et al., 2017). We have identified human Enhancer of Rudimentary Homolog (ERH) as a key regulator of H3K9me3 at both genes and repeat elements (McCarthy et al., 2021). By gaining a more detailed mechanistic understanding of H3K9me3 regulation we will be able to selectively de-repress heterochromatin, permitting effective cell identity changes to generate functional transplantable cell therapies from a patient’s own cells thus avoiding the wait for donor organs or the need for immunosuppression.
Project 2:
H3K9me3 heterochromatin regulation during development
Development successfully establishes and rearranges heterochromatin to generate a multitude of cell fates and functions; understanding this process provides new tools for manipulating cell identity. During the first stages of preimplantation cell division H3K9me3 undergoes dynamic changes to silence repetitive elements and begin lineage commitment (Wang et al., Nature Cell Biol., 2018). Later in development H3K9me3 is important to restrict cell lineage during differentiation and development (Nicetto/Zaret, Science, 2019). The mechanisms by which specific genes are targeted for heterochromatin repression and later de-repression are poorly understood. We aim to better understand H3K9me3 dynamics during development and the proteins and mechanisms responsible for establishment, maintenance, and removal of cell type specific heterochromatin distributions.