Our work is a major step forward in mapping the transcriptional regulatory circuitry in human embryonic stem (ES) cells. This is very important because human ES cells are thought to hold great promise for human medicine and are a good model system in which to study development. These cells can be propagated indefinitely in culture while maintaining pluripotency—the capacity to give rise to all cell types of the body. How ES cells could accomplish this was poorly understood.

We mapped the sets of genes occupied by three transcription factors (OCT4, SOX2, and Nanog), whose functions are essential for the earliest stages of development and for ES cell pluripotency. This work suggested that these factors contribute to the maintenance of the ES cell state by controlling genes whose expression would otherwise promote differentiation. These findings provide the foundation for learning how to modify the circuitry of embryonic stem cells to make cells for regenerative medicine or to repair damaged or diseased cells. This study also provides the foundation and tools for mapping the regulatory circuitry in all human cells.

We developed novel tools that allowed us to pinpoint the location of transcription factors throughout the human genome in order to map the core transcriptional regulatory circuitry in ES cells. This method, known as genome-wide location analysis or "ChIP on chip," combines chromatin immunoprecipitation and DNA microarrays which were designed to contain DNA sequences representing large portions of the human genome. Importantly, we were able to combine experimental and computational technologies to show how key regulators of pluripotency may control gene expression programs in ES cells.

The gene expression program in ES cells must allow these cells to remain unspecialized while maintaining the capacity to ultimately give rise to all cell types in the body—an important property for their use in human regenerative medicine.

We identified how key regulators of the ES cell gene expression program contribute to these unique characteristics. These findings have important implications for understanding human development and disease and for realizing the therapeutic potential of these remarkable cells.

I became involved in this research because I was intrigued by the remarkable properties and therapeutic potential of embryonic stem cells. I reasoned that if we could understand how ES cells were "wired," then we could better understand how to harness the potential of these cells for cell-based therapies. There were a number of obstacles along the way, as we first had to establish the experimental and computational tools to be able to address this question.

Given that human ES cells hold great promise for human medicine, it is essential to understand the biology of these cells so that their potential may be realized. Improved understanding of the regulatory circuitry should lead to new insights into disease mechanisms and the development of new diagnostics and therapeutics.

Determining how an ES cell differentiates into specialized cells might eventually allow development of methods to reprogram an adult cell to a more "pluripotent" state, which may overcome the need to use human embryos.