One of the major gaps in embryonic stem (ES) cell biology is our incomplete understanding of the mechanisms that enable the ES cells to differentiate into virtually all cell types in the body. While much progress has been made recently in determining key DNA sequences involved in ES cell differentiation, it is still unclear how such sequences work together to regulate ES cell differentiation. Based on existing evidence, we hypothesize that the way chromosomes are folded in 3-dimensional space would play a critical role in this process, but our current knowledge of chromosome folding principle is rather poor. Here, we propose to use a powerful DNA sequencing technique to analyze chromosome folding in the human ES cells before and after differentiation into four different cell types. We will carry out multiple analyses to study the role of chromatin architecture in gene regulation and ES cell differentiation. We anticipate that the proposed experiments will result in much improved understanding of the program controlling ES cell differentiation, which will translate into better means to manipulate the ES cells and development of better ES cell based therapeutics.
The proposed research will significantly improve our understanding of the mechanisms by which human ES cells differentiate along specific cell lineages. Such knowledge will facilitate the development of new methods for differentiating the ES cells and design new stem cell therapies.