Polycomb-like 2 Associates with PRC2 and Regulates Transcriptional Networks during Mouse Embryonic Stem Cell Self-Renewal and Differentiation

• Published in: Cell stem cell 2010-02, Vol.6 (2), p.153-166
• Main Authors: Walker, Emily, Chang, Wing Y., Hunkapiller, Julie, Cagney, Gerard, Garcha, Kamal, Torchia, Joseph, Krogan, Nevan J., Reiter, Jeremy F., Stanford, William L.
• Format: Article
• Language: English
• Subjects: Animals; Biological and medical sciences; Cell Differentiation; Cell differentiation, maturation, development, hematopoiesis; Cell Line; Cell physiology; Cellular Reprogramming; Down-Regulation; Embryonic Stem Cells - cytology; Embryonic Stem Cells - metabolism; Fundamental and applied biological sciences. Psychology; Gene Expression Profiling; Gene Regulatory Networks; Genome-Wide Association Study; Histones - metabolism; Methylation; Mice; Molecular and cellular biology; Molecular genetics; Pluripotent Stem Cells - cytology; Pluripotent Stem Cells - metabolism; Polycomb Repressive Complex 2; Polycomb-Group Proteins; Protein Binding; Repressor Proteins - genetics; Repressor Proteins - metabolism; STEMCELL; Transcription. Transcription factor. Splicing. Rna processing
• ISSN: 1934-5909; 1875-9777
• DOI: 10.1016/j.stem.2009.12.014

Polycomb group (PcG) proteins are conserved epigenetic transcriptional repressors that control numerous developmental gene expression programs and have recently been implicated in modulating embryonic stem cell (ESC) fate. We identified the PcG protein PCL2 (polycomb-like 2) in a genome-wide screen for regulators of self-renewal and pluripotency and predicted that it would play an important role in mouse ESC-fate determination. Using multiple biochemical strategies, we provide evidence that PCL2 is a Polycomb Repressive Complex 2 (PRC2)-associated protein in mouse ESCs. Knockdown of Pcl2 in ESCs resulted in heightened self-renewal characteristics, defects in differentiation, and altered patterns of histone methylation. Integration of global gene expression and promoter occupancy analyses allowed us to identify PCL2 and PRC2 transcriptional targets and draft regulatory networks. We describe the role of PCL2 in both modulating transcription of ESC self-renewal genes in undifferentiated ESCs as well as developmental regulators during early commitment and differentiation. ► PCL2 associates with the PRC2 complex in mouse ESCs ► PCL2 knockdown increases self-renewal and disrupts differentiation ► Reducing PLC2 decreases H3K27me3 at specific targets ► PCL2 represses transcription of self-renewal genes in ESCs