Novel integrative approach sheds light on embryonic stem cell identity
By Simone Otto
Just as every human has a unique personality, every cell type expresses a unique set of proteins necessary to its identity. In a new study published in the April issue of the journal Proceedings of the National Academy of Sciences, researchers at NIEHS reported a novel computational approach to identify genes associated with embryonic stem cell (ESC) identity.
Senthilkumar Cinghu, Ph.D., visiting fellow in the NIEHS Systems Biology Group (SBG), is lead author of the study. “Identification and characterization of genes that maintain ESC identity is a key first step toward using ESCs as models for stem cell transplantation therapies and toxicity tests,” he said.
Illuminating ESC regulation
ESCs are pluripotent, meaning they have the power to become any cell in the adult human body. During development, ESCs must be able to divide rapidly and repeatedly without acquiring mutations associated with oxidative stress, as happens in adult cells. According to the authors, this research illuminates a novel regulatory mechanism that facilitates rapid proliferation of ESCs without compromising genomic stability.
"Ever-increasing evidence, supporting the possible hijacking of stem cell self-renewal pathways by cancer stem cells, makes it all the more important to identify, characterize, and understand the pathways that control ES cell identity," said Raja Jothi, Ph.D., lead researcher on the study and head of SBG.
Assigning ranks to genes
Sailu Yellaboina, Ph.D., former visiting fellow in SGB, led the effort to develop a computational approach for systematic integration of published gene expression data, to rank-order genes based on their likelihood of defining a cell type of interest. This approach favors genes that are consistently reported in many studies to be highly expressed in ESCs — the cell type of interest in this study — and significantly down-regulated during the normal course of ESC differentiation.
“You’re basically leveraging the evidence from a number of data sets and the consistency of data sets to make a reasonably good set of predictions,” explained Jothi.
Many genes ranked as most important to determining ESC identity were also members of protein complexes known to be important in ESCs, whereas genes from complexes known to be important for cell differentiation ranked near the bottom of the order.
Nucleolin is an important shield against oxidative stress
The most exciting result was the unexpectedly high rankings of many genes that had never been implicated in ESC biology. Guang Hu, Ph.D., head of the NIEHS Stem Cell Biology Group, joined forces with Jothi and his team to validate over a dozen novel ESC regulators, including Nucleolin, a gene whose expression is particularly high in cancer cells. The researchers revealed the essential role of Nucleolin in ESC homeostasis, for its role in shielding against oxidative stress induced by redox imbalance, which can induce ESC differentiation (see image below).
“Given the similarities between ESCs and cancer cells, we expect our findings to set the stage for understanding not only tumorigenesis, but also cell fate decisions in cancer stem cells, which are widely believed to possess tumor-initiating capabilities,” Jothi said.
Citation: Cinghu S, Yellaboina S, Freudenberg JM, Ghosh S, Zheng X, Oldfield AJ, Lackford BL, Zaykin DV, Hu G, Jothi R. 2014. Integrative framework for identification of key cell identity genes uncovers determinants of ES cell identity and homeostasis. Proc Natl Acad Sci U S A 111(16):E1581-E1590.
(Simone Otto, Ph.D., is an Intramural Research and Training Award fellow in the NIEHS Ion Physiology Channel Group.)