Project Summary/Abstract
Almost every cell in a human being has the same DNA sequence yet different cells vary widely in which genes
are expressed. In addition to the genetic code, human cells contain chemical modifications on DNA called
epigenetics that can dictate cell type identity and cell fate. The most abundant epigenetic modification in the
human genome is DNA methylation, which is critical for silencing transposable elements, genomic imprinting,
and X chromosome inactivation. Aberrant DNA methylation patterns is a hallmark of aging and cancer cells,
however the genetic pathways that contribute to DNA methylation remains unclear.
My research laboratory aims to unlock how DNA methylation is established in the human genome and to
understand how defects in DNA methylation pathways leads to disease. Using genome-wide genetic screens,
my lab has recently discovered genes that previously have not been implicated in DNA methylation, including
an RNA binding protein and the proteasomal complex that degrades proteins. In the next five years, we will
dissect the roles of our newly discovered genetic factors of DNA methylation and how they regulate gene
expression programs in cancer and embryonic stem cells using multidisciplinary approaches including
biochemistry, genetics, and advances in DNA sequencing technologies.
In addition to our goals to understand DNA methylation pathways, my laboratory is a leader in pioneering new
CRISPR methods to write and erase DNA methylation at any site in the genome. We use lessons learned from
our basic biology findings to engineer tools that allow us to turn off/on human genes solely by changing the
epigenetics of a gene instead of inducing harmful DNA breaks. In the next five years, we will innovate next
generation CRISPR epigenetic editing technologies that enables fine tuning of transcription at defined levels. To
overcome the current challenge of delivering CRISPR technologies into primary human cells, we will establish
the first protein-based delivery of CRISPR epigenetic editing technologies into primary immune cells for use in
cancer immunotherapy applications. Our CRISPR epigenetic editing technologies and delivery platforms will
have broad use in the biomedical sciences and as safe and robust tools for cell and gene therapy clinical
applications purely by modifying epigenetics instead of genome editing.