The trithorax and the polycomb group proteins are chromatin modifiers, which play a key role in the epigenetic regulation of development, differentiation and maintenance of cell fates. The polycomb repressive complex 2 (PRC2) mediates transcriptional repression by catalysing the di- and tri-methylation of Lys 27 on histone H3 (H3K27me2/me3). Owing to the essential role of the PRC2 complex in repressing a large number of genes involved in somatic processes, the H3K27me3 mark is associated with the unique epigenetic state of stem cells. The rapid decrease of the H3K27me3 mark during specific stages of embryogenesis and stem-cell differentiation indicates that histone demethylases specific for H3K27me3 may exist. Here we show that the human JmjC-domain-containing proteins UTX and JMJD3 demethylate tri-methylated Lys 27 on histone H3. Furthermore, we demonstrate that ectopic expression of JMJD3 leads to a strong decrease of H3K27me3 levels and causes delocalization of polycomb proteins in vivo. Consistent with the strong decrease in H3K27me3 levels associated with HOX genes during differentiation, we show that UTX directly binds to the HOXB1 locus and is required for its activation. Finally mutation of F18E9.5, a Caenorhabditis elegans JMJD3 orthologue, or inhibition of its expression, results in abnormal gonad development. Taken together, these results suggest that H3K27me3 demethylation regulated by UTX/JMJD3 proteins is essential for proper development. Moreover, the recent demonstration that UTX associates with the H3K4me3 histone methyltransferase MLL2 (ref. 8) supports a model in which the coordinated removal of repressive marks, polycomb group displacement, and deposition of activating marks are important for the stringent regulation of transcription during cellular differentiation.
Enzymes catalysing the methylation of the 5-position of cytosine (mC) have essential roles in regulating gene expression and maintaining cellular identity. Recently, TET1 was found to hydroxylate the methyl group of mC, converting it to 5-hydroxymethyl cytosine (hmC). Here we show that TET1 binds throughout the genome of embryonic stem cells, with the majority of binding sites located at transcription start sites (TSSs) of CpG-rich promoters and within genes. The hmC modification is found in gene bodies and in contrast to mC is also enriched at CpG-rich TSSs. We provide evidence further that TET1 has a role in transcriptional repression. TET1 binds a significant proportion of Polycomb group target genes. Furthermore, TET1 associates and colocalizes with the SIN3A co-repressor complex. We propose that TET1 fine-tunes transcription, opposes aberrant DNA methylation at CpG-rich sequences and thereby contributes to the regulation of DNA methylation fidelity.
The Polycomb group (PcG) proteins form chromatin-modifying complexes that are essential for embryonic development and stem cell renewal and are commonly deregulated in cancer. Here, we identify their target genes using genome-wide location analysis in human embryonic fibroblasts. We find that Polycomb-Repressive Complex 1 (PRC1), PRC2, and tri-methylated histone H3K27 co-occupy >1000 silenced genes with a strong functional bias for embryonic development and cell fate decisions. We functionally identify 40 genes derepressed in human embryonic fibroblasts depleted of the PRC2 components (EZH2, EED, SUZ12) and the PRC1 component, BMI-1. Interestingly, several markers of osteogenesis, adipogenesis, and chrondrogenesis are among these genes, consistent with the mesenchymal origin of fibroblasts. Using a neuronal model of differentiation, we delineate two different mechanisms for regulating PcG target genes. For genes activated during differentiation, PcGs are displaced. However, for genes repressed during differentiation, we paradoxically find that they are already bound by the PcGs in nondifferentiated cells despite being actively transcribed. Our results are consistent with the hypothesis that PcGs are part of a preprogrammed memory system established during embryogenesis marking certain key genes for repressive signals during subsequent developmental and differentiation processes.[Keywords: Polycomb; chromatin; epigenetics; stem cells; differentiation] Supplemental material is available at http://www.genesdev.org.
The p16INK4A and p14 ARF proteins, encoded by the INK4A-ARF locus, are key regulators of cellular senescence, yet the mechanisms triggering their up-regulation are not well understood. Here, we show that the ability of the oncogene BMI1 to repress the INK4A-ARF locus requires its direct association and is dependent on the continued presence of the EZH2-containing PolycombRepressive Complex 2 (PRC2) complex. Significantly, EZH2 is down-regulated in stressed and senescing populations of cells, coinciding with decreased levels of associated H3K27me3, displacement of BMI1, and activation of transcription. These results provide a model for how the INK4A-ARF locus is activated and how Polycombs contribute to cancer. Cellular senescence is an irreversible growth arrest triggered by several types of stress, including DNA damage, telomere shortening, and oncogene activation (Dimri 2005). Recently, its relevance as a bona fide tumor-suppressive mechanism in vivo has been highlighted (for review, see Narita and Lowe 2005). The Polycomb group (PcG) proteins BMI1, CBX7, and CBX8 are capable of delaying the onset of senescence in mouse and human embryonic fibroblasts (MEFs and HEFs) (Jacobs et al. 1999;Gil et al. 2004;Dietrich et al. 2007). This has been shown to correlate with a decrease in the levels of p16 INK4A and, in some cases, p14 ARF (p19 Arf in mice). Both of these proteins are encoded by the INK4A-ARF locus and are tumor suppressors that act upstream of the pRB and p53 pathways, respectively (Lowe and Sherr 2003).The BMI1-containing Polycomb-Repressive Complex 1 (PRC1), of which many variants are thought to exist, also contains the CBX (CBX2, CBX4, CBX6, CBX7, and CBX8), PHC1-3, RNF1-2, and SCML1-2 proteins (Levine et al. 2004). A second complex, PRC2, contains the histone methyltransferase EZH2, which together with EED and SUZ12 trimethylates histone H3 on Lys 27 (H3K27me3) (Cao and Zhang 2004;Pasini et al. 2004b). The ability of PRC1 to bind to chromatin is dependent on PRC2 function, and it has been proposed that this is primarily achieved via binding to the H3K27me3 mark (Rastelli et al. 1993;Hernandez-Munoz et al. 2005).In this study, we address several outstanding questions concerning the regulation of the INK4A-ARF locus by BMI1. We establish that BMI1 together with other PcGs and the associated H3K27me3 mark "blanket" the locus both in vivo and in vitro (tissue culture) in both mouse and human cells. We show that the repression of the locus by BMI1 is dependent on the continued association of the EZH2-containing PRC2 complex and that the levels of EZH2 are down-regulated in stressed and senescent cells. This down-regulation leads to the loss of H3K27me3, displacement of BMI1, and activation of INK4A transcription, resulting in senescence. Taken together, our results provide a model for how the INK4A-ARF locus is regulated in response to multiple cellular signals and how increased expression of the PcGs contributes to cancer. Results and Discussion PcGs and associated H3K27me3 'blanket' the INK4A-ARF locus ...
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