Researchers from the Differentiation and Cancer group of the Center for Genomic Regulation (CRG) have published an innovative study on the role of Cbx proteins in the genetic regulation of embryonic stem cells. The study revealed that changes in the expression of specific Polycomb group proteins modulate the function of the Polycomb complex during both embryonic stem cell differentiation and tumorigenesis.
The Polycomb repressive complex 1 (PRC1) regulates the proliferation, and the subsequent differentiation into somatic cells, of embryonic stem (ES) cells, but the exact role of the different Polycomb proteins in this complex has been a long-standing puzzle. Researchers at the CRG have now elucidated the role that several specific Polycomb proteins (namely, Cbx2, -4, -6, -7, and -8) play during cell development through their incorporation into, and regulation by, the PRC1 complex. This discovery represents a breakthrough in understanding both how stem cells proliferate and which specific functions the Cbx proteins and the Polycomb PRC1 complex play during tumor development. Identifying new proteins that are essential for maintaining ES cell pluripotency is a key step in elucidating tumor formation processes and in advancing regenerative medicine.
Since its incorporation into the CRG, the group of Epigenetic Events in Cancer, lead by Dr. Luciano Di Croce, has focused on the biological functions of the Polycomb complex and its role during tumor progression. They have previously made important contributions to the field and have published articles in high impact journals such as Cancer Cell (in 2007) and Nature (in 2010). Now, they have tackled the question of how ES cell regulation by the Polycomb group proteins and complexes is fine-tuned: while it has been long known that this regulation occurs, nothing was known about whether the individual Polycomb proteins have specific functions. They discovered that, indeed, different Cbx proteins have distinct functions that can modulate the activity of the PRC1 complex, as they report in their article to be published in Cell Stem Cell on 6 January 2012.
ES cells are key for embryonic development. ES cells can divide (proliferate) extensively before they differentiate into the somatic cells that form the adult tissue. "We found that the protein Cbx7 is present during the proliferation phase, when the cells still maintain their pluripotency, but that Cbx7 is replaced with Cbx2 and Cbx4 during the differentiation phase. Exchanging one Cbx protein for another has important consequences for the pluripotent capacity of ES cells, tumor formation, and correct cellular differentiation," says Lluis Morey, first author of the paper.
"We discovered that implanting ES cells depleted for the different specific Cbx proteins led to the mice developing tumors with different characteristics. This showed that each Cbx protein has a unique function. Even though there is no medical application at the present time, these results will surely generate research towards developing drugs that could block these type of proteins," said Dr. Di Croce, ICREA Investigator and corresponding author of the study.
The study was done in collaboration with the CRG group of Epithelial Homeostasis and Cancer, headed by Dr. Salvador Aznar-Benitah, ICREA Investigator, and with Dr. Anton Wutz, from the Wellcome Trust Centre for Stem Cell Research, Cambridge. It was supported by grants from the Spanish ''Ministerio de Educación y Ciencia'' (CONSOLIDER program), the AGAUR, and a postdoctoral CRG-Novartis fellowship.
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