Stem Cell Research
Robert D. Kornberg’s work in revealing the structure and possible mechanisms of eukaryotic RNA polymerase II and its associated factors has contributed greatly stem cell research. Embryonic stem (ES) cells are undifferentiated cells derived from the inner cell mass (ICM) of early developmental blastocyst cells. Totipotent (potential for all) cells are those that can give rise to any type of cell. Instead, ES cells can are considered pluripotent (potential for many), because they can give rise to about 200 different types of cells. Transcriptional mechanisms are thought to regulate ES cell differentiation. Therefore, understanding what components are involved and how the mechanisms work are areas of research that hold great therapeutic potential in regenerative medicine.
Regulators are proteins that bind to DNA and either activate or repress gene expression. Homeodomain transcription factors OCT4, Sox2, and NANOG are known as the key regulators that ensure appropriate differentiation of all ES and ICM cells (10). It is thought that developmental genes and the genes of their specific regulators are in close proximity of one another. Therefore, OCT4, Sox2, and NANOG can influence the differentiation of most cells by regulating the regulators of developmental genes at the appropriate time and place. A genome-scale location analysis was used to locate the genes of OCT4, Sox2, and NANOG. This analysis showed that these three genes are located within the same region of promoters in a large population of human genes. Moreover, these target genes (part of the large population) encode homeodomain transcription factors that regulate developmentally-important genes.
Regulators can control the levels of expressed product by using either positive and negative feedback loops. Positive feedback occurs when the absence of a product causes the activation of gene expression. Negative feedback occurs when too much product represses gene expression. As stated above, OCT4, Sox2, or NANOG (primary regulators) regulates the expression of regulatory proteins (secondary regulators). This unique system of regulation, also called a feedforward loop, has an additional feature that allows both regulators to bind to the same target genes. As a result, the two regulators can give rise to different combinations to positive and negative feedback loop functions. This extra level of control may explain how OCT4, Sox2, and NANOG can keep ES cells pluripotent while still responsive to signals that trigger differentiation.