Every cell in the human body shares the same DNA sequence, but they differ in their functions. For instance, a cardiac muscle cell is uniquely qualified to contract and relax in order to pump blood through the heart, while a skin cell is particularly skilled at keeping what should be in our bodies on the inside and everything else on the outside.
How a stem cell — the progenitor cell that gives rise to all the differentiated cell types in the body — commits to one cellular lineage over another is determined by the interplay of multiple regulatory layers. It is also reflected in the unique epigenome of each cell type: the collection of molecular and structural modifications on top of the genome, which put individual genes into physical states that make them more or less likely to be expressed.
Stem cells, and induced pluripotent stem (iPS) cells in particular (cells pushed backward in their development), provide an unprecedented opportunity to investigate the dynamic nature of cell identity and the relationships between gene regulation and differentiation. With iPS cell models, researchers can follow changes in a differentiating cell's epigenomic state over time, observations that reveal the positions of important regulatory elements and pinpoint the roles they may play in specific differentiation paths.
Comparing those observations across lineages (e.g., neuron to cardiomyocyte to hepatocyte) and perturbing specific regulatory elements with genome editing or gene silencing tools can yield additional, comprehensive insights into the epigenomic rules governing genome function and cell fate.
Here at the Broad, we characterize cells’ epigenetic landscapes at different stages of early development and observe how these factors determine their evolution. And we have developed powerful new approaches that allow us to ask these questions of individual cells. We also take advantage of pluripotent iPS and embryonic stem cells that can be differentiated in vitro to understand the process of human development.
This work also has major implications for understanding human disease. By understanding development, we can learn about the mechanisms that are active in different pathological situations. (Cancer, for instance, arises in part due to the inappropriate persistence of cells in immature differentiation states). We can also use the epigenome to understand diseases like muscular dystrophy, which is thought to result, in part, from deficiencies in muscle stem cell production.
If we can better understand normal human development — for example, by pushing a developed cell backward in its differentiation or by looking at the process of differentiation at different time points along the way — we can start to understand what goes wrong in disease states.
Pluripotency and lineage specification
To study cellular pluripotency and lineage specification we perform extensive transcriptional and epigenomic profiling of human embryonic stem cells and in vitro differentiated cell populations. To assemble the gene-regulatory networks governing the cell-type specific epigenomes and gene-expression profiles, we employ massively parallel reporter assays to measure the activities of thousands of putative enhancer elements and use computational and experimental approaches to identify transcription factors that drive their activities and determine their downstream gene targets.
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Yu VW, Yusuf RZ, et al. Epigenetic Memory Underlies Cell-Autonomous Heterogeneous Behavior of Hematopoietic Stem Cells. Cell. 2017.
Tsankov AM, Gu H, et al. Transcription factor binding dynamics during human ES cell differentiation. Nature. 2015.
Ziller MJ, Edri R, et al. Dissecting neural differentiation regulatory networks through epigenetic footprinting. Nature. 2015.
Gifford CA, Ziller MJ, et al. Transcriptional and epigenetic dynamics during specification of human embryonic stem cells. Cell. 2013.