Project description:Polycomb repressive complex 2 (PRC2-EZH2) methylates histone H3 at lysine 27 (H3K27) and is required to maintain gene repression during development. Misregulation of PRC2 is linked to a range of neoplastic malignancies, which is believed to involve methylation of H3K27. However, the full spectrum of non-histone substrates of PRC2 that might also contribute to PRC2 function is not known. We characterized the target recognition specificity of PRC2 and used the resultant data to screen for novel potential targets. The RNA polymerase II (Pol II) transcription factor, Elongin A (EloA), is methylated by PRC2 in vivo. Mutation of the methylated EloA residue decreased repression of many, but not all, PRC2 target genes as measured by both steady state and nascent RNA levels. We propose that PRC2 regulates transcription of a subset of target genes in part via methylation of EloA.
Project description:Polycomb repressive complex 2 (PRC2-EZH2) methylates histone H3 at lysine 27 (H3K27) and is required to maintain gene repression during development. Misregulation of PRC2 is linked to a range of neoplastic malignancies, which is believed to involve methylation of H3K27. However, the full spectrum of non-histone substrates of PRC2 that might also contribute to PRC2 function is not known. We characterized the target recognition specificity of PRC2 and used the resultant data to screen for novel potential targets. The RNA polymerase II (Pol II) transcription factor, Elongin A (EloA), is methylated by PRC2 in vivo. Mutation of the methylated EloA residue decreased repression of many, but not all, PRC2 target genes as measured by both steady state and nascent RNA levels. We propose that PRC2 regulates transcription of a subset of target genes in part via methylation of EloA.
Project description:Polycomb repressive complex 2 (PRC2-EZH2) methylates histone H3 at lysine 27 (H3K27). PRC2 is required to maintain gene repression during development and differentiation and misregulation of PRC2 is linked to a range of neoplastic malignancies, activities that are believed to involve H3K27 methylation. The full spectrum of non-histone substrates of PRC2, however, is not known, and it is not known which other substrates might also contribute to the biological functions of PRC2. We characterized the target recognition specificity and substrate diversity of PRC2, and identified more than one hundred potential novel nuclear targets of PRC2. The RNA polymerase II (Pol II) transcription elongation factor, Elongin A (EloA), is an in vivo target of PRC2. Mutation of the EloA residue that is methylated by PRC2 decreases repression of numerous PRC2 target genes. We propose that this functional crosstalk between PRC2 and EloA tunes the level of repression of targeted genes and contributes to the biological functions of PRC2.
Project description:The cellular plasticity of pluripotent stem cells is thought to be sustained by genomic regions that display both active and repressive chromatin properties. These regions exhibit low levels of gene expression, yet the mechanisms controlling these levels remain unknown. Here, we describe Elongin BC as a binding factor at the promoters of bivalent sites. Biochemical and genome-wide analysis shows that Elongin BC is associated with Polycomb Repressive Complex 2 (PRC2) in pluripotent stem cells. Elongin BC is recruited to chromatin by the PRC2-associated factor EPOP (Elongin- and POlycomb-associated Protein, also termed C17orf96, esPRC2p48, E130012A19Rik), a protein expressed in the inner cell mass of the mouse blastocyst. Both EPOP and Elongin BC are required to maintain low levels of expression at PRC2 genomic targets. Our results indicate that keeping the balance between activating and repressive cues is a more general feature of chromatin in pluripotent stem cells than previously appreciated.
Project description:We show that Polycomb repressive complexes (PRCs) regulate lineage choice between neural and non-neural fates in the olfactory epithelium. Conditional loss of Polycomb repressive complex 2 perturbs lesion-induced neurogenesis and misexpression of lineage-specific transcription factors in multipotent olfactory globose basal cells.
Project description:We show that Polycomb repressive complexes (PRCs) regulate lineage choice between neural and non-neural fates in the olfactory epithelium. Conditional loss of Polycomb repressive complex 2 perturbs lesion-induced neurogenesis and misexpression of lineage-specific transcription factors in multipotent olfactory globose basal cells.