Current Research
I. Cell fate model systems:
Fertilization of gametes (cells with a lineage) produces a totipotent cell (can form ALL cell types of both the embryo and extra-embryonic tissue). As embryogenesis proceeds, developmental potential diminishes. Within the blastocyst, cells are pluripotent (can only form the embryo), followed by the development of more specialized cell types.
Amazingly, these developmental states can be captured in vitro. We utilize dynamic cell fate transitions as a model system to understand how identity is established and regulated.
For example, unipotent (terminally differentiated) cells can be “pushed back” to pluripotency by the expression of reprogramming factors. Unipotent cells can also be transdifferentiated directly to other somatic cell types. In the opposite direction, pluripotent cells can be differentiated to cells with less developmental potential.
II. Decoding the epigenetic contribution to developmental disorders:
How is the epigenome interpreted to specify cell fate? “Reader” proteins recognize and bind epigenetic modifications to recruit effectors like transcriptional machinery, remodelers, and more. Variants in readers have been identified in developmental disorders like Rett syndrome and Cornelia de Lange syndrome.
We use cutting edge genome editing to introduce clinical variants coupled with traditional molecular biology approaches to tease apart these tightly interwoven epigenetic-transcriptional networks.
III. Uncovering the cancer epigenome
Epigenetic readers are commonly mutated in childhood cancers like acute leukemia and Wilm’s tumor. We employ differentiation of embryonic stems cells carrying cancer mutations to uncover how the epigenome is misinterpreted in “real-time” throughout lineage acquisition. Analysis starting from this epigenetic blank-slate is a unique strategy to isolate the earliest stages of oncogenesis missed in traditional studies.
