The findings, published in the Dec. 15 issue of the peer-reviewed journal Genes and Development, provide important new insights into a class of genes whose properties previously were assumed to be unimportant for stem cell function.
While most research has focused on the genes that regulate pluripotency networks and the genes that regulate the differentiation of embryonic stem cells into other cell lineages, the UCLA researchers focused on this third class of genes, which are expressed only in defined cell types or tissues and remain silent until long after embryonic stem cells have differentiated into specific cell lineages.
“Although prior models suggested that the cascade of events leading to the activation of tissue-specific genes doesn’t begin until embryonic stem cells have differentiated, our findings support a new hypothesis in which the competence of these genes for expression is dependent on specific marks established in the pluripotent state,” said senior study author Stephen Smale, UCLA professor of microbiology, immunology and molecular genetics. “If this hypothesis is correct, the proper marking of tissue-specific genes may be essential for pluripotency and the efficient differentiation of stem cells into clinically usable cell types and tissues.”
Prior to this study, typical tissue-specific genes were believed to have no critical interactions and to exist in a base state in embryonic stem cells, sitting silently in the cell and waiting to be “marked” by proteins that set in motion a series of molecular events. However, Smale and his team unexpectedly identified protein marks on these genes in stem cells and obtained striking evidence that the absence of these stem cell marks compromises gene expression in stem cell–derived tissues. The finding that these genes were already marked was surprising, Smale said.
“This finding may help us understand what it really means to be pluripotent,” Smale said. “True pluripotency may depend on faithful marking in pluripotent stem cells of many or all genes within the human genome.”
This could be particularly important for those seeking to use embryonic stem cells or reprogrammed cells, called induced pluripotent stem (iPS) cells, to treat diseases or in regenerative medicine. The stem cell marks may ensure that the end result — a beta cell to treat diabetes, a neuron for Parkinson’s disease or a cardiac cell for heart problems — is a fully functional cell operating at 100 percent of its potential.
“We really do need to pay attention to these genes at the outset,” Smale said. “Although silent in stem cells, their properties appear to be very important.”
This study was funded by a grant from the National Institutes of Health and a training grant from the California Institute of Regenerative Medicine to Jian Xu, lead author on the study. Other key participants included Kenneth Zaret from the University of Pennsylvania and Kathrin Plath from UCLA’s Broad Stem Cell Research Center.
The Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research: UCLA’s stem cell center was launched in 2005 with a UCLA commitment of $20 million over five years. A $20 million gift from the Eli and Edythe Broad Foundation in 2007 resulted in the renaming of the center. With more than 200 members, the Broad Stem Cell Research Center is committed to a multidisciplinary, integrated collaboration among scientific, academic and medical disciplines for the purpose of understanding adult and human embryonic stem cells. The center supports innovation, excellence and the highest ethical standards focused on stem cell research with the intent of facilitating basic scientific inquiry directed toward future clinical applications to treat disease. The center is a collaboration of the David Geffen School of Medicine at UCLA, UCLA’s Jonsson Cancer Center, the UCLA Henry Samueli School of Engineering and Applied Science and the UCLA College of Letters and Science.