title: PCL2 modulates gene regulatory networks controlling self-renewal and commitment in embryonic stem cells.
abstract: Recent reports have better elucidated the components of the Polycomb Repressive Complex 2 (PRC2) and its functional role in embryonic stem cells (ESCs) and their differentiated derivatives. The depletion of a newly described mammalian PRC2 associated protein, PCL2, leads to an increase in ESC self-renewal and a delay in differentiation, a phenotype similar to knockouts of the core PRC2 members. Genomic and cell biology data suggest that PCL2 is important in cell fate decisions and may play a role in recruitment of PRC2 to target genes and histone methylation. Importantly, depletion of PCL2 in ESCs leads to a decrease in 3meH3K27 at the proximal promoter regions of pluripotency transcription factors Tbx3, Klf4, Foxd3 and a concomitant increase in gene expression. These proteins subsequently activate expression of Oct4, Nanog and Sox2 through a feed-forward gene regulatory circuit, altering the core pluripotency network and driving cell fate decisions towards self-renewal. We propose a model whereby alteration of the epigenetic state of Tbx3, Klf4, and Foxd3 results in the enforced expression of the pluripotency network, preventing differentiation.
authors.affiliation: Institute of Biomaterials and Biomedical Engineering, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Emily
authors.initials: E
authors.lastname: Walker
authors.forename: Janet L
authors.initials: JL
authors.lastname: Manias
authors.forename: Wing Y
authors.initials: WY
authors.lastname: Chang
authors.forename: William L
authors.initials: WL
authors.lastname: Stanford
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002454:Cell Differentiation / Q000502:physiology; D016213:Cyclins / Q000502:physiology; D029721:Drosophila Proteins / Q000502:physiology*; D053595:Embryonic Stem Cells / Q000166:cytology / Q000502:physiology*; D053263:Gene Regulatory Networks / Q000502:physiology*; D011495:Histone-Lysine N-Methyltransferase / Q000502:physiology*; D006801:Humans; D000090062:Kruppel-Like Factor 4; D008969:Molecular Sequence Data; D063146:Polycomb-Group Proteins; D012097:Repressor Proteins / Q000502:physiology; D029701:Saccharomyces cerevisiae Proteins / Q000502:physiology
chemical_list: D016213:Cyclins; D029721:Drosophila Proteins; C000715467:KLF4 protein, human; D000090062:Kruppel-Like Factor 4; C090559:PCL2 protein, S cerevisiae; D063146:Polycomb-Group Proteins; D012097:Repressor Proteins; D029701:Saccharomyces cerevisiae Proteins; D011495:Histone-Lysine N-Methyltransferase; C524066:PRC2 protein, Drosophila