Genome-wide mapping of Polycomb target genes unravels their roles in cell fate transitions.

By A. Bracken, Nikolaj Dietrich, Diego Pasini, K. Hansen, K. Helin. Genes & Development, 2006

1,354 citations recorded by the source corpus.

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.

Subfields: Molecular Biology

View Paper: https://www.semanticscholar.org/paper/bfa3586d90572ab6b9a442b30c9a5e7f348a94ac

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Citations in the corpus

The Polycomb Complex PRC2 and its Mark in Life (2011, background): “PRC2 specifically resides at — and targets for H3K27me3 deposition — the Hox genes and numerous genes encoding other developmental regulator”
Repression of E-cadherin by the polycomb group protein EZH2 in cancer (2008, background): “In human and mouse embryonic stem cells, as well as in Drosophila, Polycomb Group (PcG) proteins contribute to pluripotency and plasticity through repression of developmental transcriptional factors that normally promote differentiation (Boyer et al., 2006; Bracken et al., 2006; Lee et al., 2006; To”
Whole-genome mapping of histone H3 Lys4 and 27 trimethylations reveals distinct genomic compartments in human embryonic stem cells. (2007, background): “Specifically, methylations of lysine 4 (K4) and 27 (K27) on histone H3 have been shown to associate with active and repressed gene expression, respectively ( Bracken et al., 2006; Kirmizis et al., 2004).”
Discovering Motifs in Ranked Lists of DNA Sequences (2007, methodology): “To further establish this link we applied DRIM to Polycomb complex bound promoters in human embryonic ﬁbroblasts [44].”
Polycomb silencers control cell fate, development and cancer (2006, background): “In accordance with the idea that the oncogenic effect of PcG proteins involves targets other than CDKN2A , a significant proportion of the recently identified PcG target genes are silenced in human tumours by DNA methylation of their promoter regio”
Control of cell identity genes occurs in insulated neighborhoods in mammalian chromosomes (2014, neutral): “Van Bortle K, Ramos E, Takenaka N, Yang J, Wahi JE, Corces VG. Drosophila CTCF tandemly aligns with other insulator proteins at the borders of H3K27me3 domains.”
Polycomb group proteins: navigators of lineage pathways led astray in cancer (2009, neutral): “The genome-wide mapping of PcG target genes in mammalian cells has offered scientists the opportunity to start to unravel the molecular mechanisms of PcG protein actio”
The Polycomb group proteins bind throughout the INK4A-ARF locus and are disassociated in senescent cells. (2007, methodology): “…Santa Cruz Biotechnology), anti-macroH2A (07-219; Upstate Biotechnology), antiH3K4Me3 (ab8580; Abcam), an equal mix of anti-CBX8 “LAST” and “GALD” (Bracken et al. 2006), an equal mix of anti-CBX7 “GAPEL” and “RELF” described above, and mouse monoclonals specific for EZH2 (AC22) (Pasini et al.…”
The nuclear deubiquitinase BAP1 is commonly inactivated by somatic mutations and 3p21.1 losses in malignant pleural mesothelioma (2011, neutral): “Comparison of this gene list to three published lists of PRC target gene”
Polycomb group proteins: multi-faceted regulators of somatic stem cells and cancer. (2010, neutral): “Importantly, these repressed PcG target genes are preferentially activated during ESC differentiation (Boyer et al., 2006; Bracken et al., 2006; Lee et al., 2006; Stock et al., 2007; Tolhuis et al., 2006).”
Inaugural Article: A PHD-Polycomb Repressive Complex 2 triggers the epigenetic silencing of FLC during vernalization (2008, neutral): “This widespread distribution of VRN2 over FLC is unlike the localized Su(z)12 at Polycomb Response Elements in Drosophila Hox genes (29, 30) and is more similar to the ‘‘blanket type’’ binding of SUZ12 at the Hox loci in proliferating human embryonic fibroblasts (31) and at genes encoding developmen”