Embryonic stem cell biology and development are regulated by epigenetic mechanisms of gene expression involving chromatin modifying enzymes that promote DNA and histone modifications. We utilize embryonic stem cells (ESCs), induced pluripotent stem cells (iPSCs) and mice as model systems to study how these enzymes reshape the epigenome and control gene expression programs to regulate stem cell biology and embryogenesis. The lab specializes in advanced technologies in genome editing and generating complex mouse strains. We integrate genetic, cellular, molecular, biochemical and bioinformatics approaches to dissect epigenetic pathways and mechanisms in stem cells, during development and in diseases.
The Tet family of enzymes (Tet1/2/3) modify the DNA base 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC) to promote DNA demethylation and gene expression. They are abundant in various cell types including the zygote, ESCs, germ cells, hematopoietic stem cells (HSCs) and neural stem cells (NSCs). Over the years, our work in the field has defined key functions of Tet enzymes in ESC differentiation, germ cell reprogramming and development (Cell Stem Cell 2011, Dev. Cell 2013, Dev. Cell 2014, Cell Reports 2019, Nucleic Acid Res. 2022, iScience 2023) as well as in hematopoiesis (Nat. Immunology 2015, Cell Reports 2015, Cell Reports 2019, Science Adv. 2022, Exp Hemaotology 2023) and in the brain (Neuron 2013, Front Cell Dev Bio 2021). Recently in my lab:
· We have shown that the biological roles of Tet enzymes go beyond their enzymatic activity in DNA demethylation. Such non-canonical functions present a novel layer of epigenetic regulation. We study their roles in ESC pluripotency and development, as well as in hematopoietic stem cells and hematologic malignancies.
· We have established that Tet enzymes regulate lineage specification and organogenesis. We research their biologically critical functions in post gastrulation development, in particular during embryonic hematopoiesis and neurodevelopment.
· We study the Tet-modified base 5hmC and its derivatives 5fC and 5caC to establish their invovlements in regulation of gene expression during development and in onset of diseases.
Our work defines how stem cell biology and development are regulated by the DNA modifying enzymes. It will unveil new mechanisms of epigenetic regulation by Tets/5hmC, and can lead to identification of unique markers and targets for stem cell applications and treatment of diseases.
For more details on our research please visit our lab website: https://www.dawlatylaboratory.com