Current Research
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.
Decoding the epigenetic contribution to development:
Reprogramming somatic cells to induced Pluripotent Stem Cells (iPSCs) results in a dramatic reorganization of the epigenome (Sridharan et al., Nat Cell Biol., 2013; Apostolou and Hochedlinger, Nature, 2013 ). Altering the epigenome to resemble pluripotent stem cells, such as globally reducing H3K79me2, greatly enhances reprogramming efficiency to iPSCs (Wille and Sridharan, Stem Cell Reports, 2020; Wille and Sridharan, Front Cell Dev Biol., 2022). Therefore, the epigenome is an important driver of cellular identity.
Decoding the precise function of epigenetic marks is challenging as one modification may have both positional and cell specific effects. Epigenetic modifications can regulate the binding of transcription factors (permissive state), histone compaction (accessibility), other epigenetic modifications, etc. We use cutting edge genomic studies coupled with traditional molecular biology approaches to tease apart these tightly interwoven epigenetic-transcriptional networks.
Uncovering the cancer epigenome:
We also employ the reprogramming of cancer cells to iPSCs as a tool to erase the “transformed identity.” Differentiation of cancer iPSCs initiates the re-establishment of the cancer epigenome directed by the underlying genetic mutations. Analysis starting from this epigenetic blank-slate is a unique strategy to isolate the earliest stages of oncogenesis missed in traditional studies.
