Developing a global understanding of the PRC and NuRD complexes in stem cell differentiation and in disease

RyBP and Cbx7 define specific biological functions of Polycomb complexes in mouse embryonic stem cells — Di Croce lab (2013)

Tuning Stem Cell Fate

The research group of Luciano Di Croce, from the Center for Genomic Regulation (CRG) in Barcelona (Spain), has discovered that RYBP and CBX7, two proteins essential for gene regulation, are at the heart of the most critical decision faced by an embryonic stem cells: what type of cells to become. These findings, published in Cell Reports, shed light on the molecular mechanisms involved in stem cell biology.

Luciano Di Croce and Lluis Morey

Stem cells are the precursors of our tissue and organs. Using them could be highly promising for regenerative medicine, yet little is known about the mechanisms that regulated the potential of stem cells to give rise to the different cell types within organisms. The Polycomb repressive complex 1 (PRC1) is an epigenetic regulator essential for stem cell function and cancer progression. It has only recently become clear that PRC1 comes in different flavors, depending on which specific proteins are incorporated into it (such as either CBX7 or RYBP). However, whether or not these PRC1 subtypes carry out different biological functions was unclear. This work has taken an important step in clarifying this question.

Using the most advanced sequencing technology, Lluis Morey, Luigi Aloia, Luciano Di Croce, and coworkers analyzed 2.64 billion DNA nucleotides of DNA from mouse embryonic stem cells to determine which regions are controlled by PRC1-RYBP as compared to PRC1-CBX7. Both complexes shared some biological functions. Surprisingly, however, the two complex subtypes also performed distinct functions. “We were able to show that these two complex subtypes can have different roles, with one involved more in metabolism and the other more in development”, commented Morey. Understanding the extent to which the different PCR1 subtypes carry out the critical decisions that determine cell fate presents the next large goal. “We are lucky to be able to address these questions within a network of experts in our FP7 4DCellFate project, since we believe that the answers will be important for understanding how to implement stem cells into therapeutic applications”, stated Di Croce.



RyBP and Cbx7 define specific biological functions of Polycomb complexes in mouse embryonic stem cells

L. Morey, L. Aloia, L. Cozzuto, S. Aznar Benitah, and L. Di Croce


Summary: The Polycomb repressive complex 1 (PRC1) is required for decisions of stem cell fate. In mouse embryonic stem cells (ESCs), two major variations of PRC1 complex, defined by the mutually exclusive presence of Cbx7 or RYBP, have been identified. Here, we show that although the genomic localization of the Cbx7- and RYBP-containing PRC1 complexes overlaps in certain genes, it can also be mutually exclusive. At the molecular level, Cbx7 is necessary for recruitment of Ring1B to chromatin, whereas RYBP enhances the PRC1 enzymatic activity. Genes occupied by RYBP show lower levels of Ring1B and H2AK119ub and are consequently more highly transcribed than those bound by Cbx7. At the functional level, we show that genes occupied by RYBP are primarily involved in the regulation of metabolism and cell-cycle progression, whereas those bound by Cbx7 predominantly control early-lineage commitment of ESCs. Altogether, our results indicate that different PRC1 subtypes establish a complex pattern of gene regulation that regulates common and non-overlapping aspects of ESC pluripotency and differentiation.

Cell Reports (2013) 3:60-69; doi: 10.1016/j.celrep.2012.11.026



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