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• W2071184971 abstract "A new study in this issue of Molecular Cell (Eskeland et al., 2010Eskeland R. Leeb M. Grimes G.R. Kress C. Boyle S. Sproul D. Gilbert N. Fan Y. Skoultchi A.I. Wutz A. Bickmore W.A. Mol. Cell. 2010; 38 (this issue): 452-464Abstract Full Text Full Text PDF PubMed Scopus (380) Google Scholar) implicates Polycomb repressive complex 1 (PRC1) in compacting Hox gene chromatin in mouse embryonic stem cells and suggests that compaction, rather than histone tail ubiquitylation, confers Hox gene silencing. A new study in this issue of Molecular Cell (Eskeland et al., 2010Eskeland R. Leeb M. Grimes G.R. Kress C. Boyle S. Sproul D. Gilbert N. Fan Y. Skoultchi A.I. Wutz A. Bickmore W.A. Mol. Cell. 2010; 38 (this issue): 452-464Abstract Full Text Full Text PDF PubMed Scopus (380) Google Scholar) implicates Polycomb repressive complex 1 (PRC1) in compacting Hox gene chromatin in mouse embryonic stem cells and suggests that compaction, rather than histone tail ubiquitylation, confers Hox gene silencing. The Polycomb group (PcG) proteins are a highly conserved set of transcriptional repressors that function via chromatin modification (Simon and Kingston, 2009Simon J.A. Kingston R.E. Nat. Rev. Mol. Cell Biol. 2009; 10: 697-708Crossref PubMed Google Scholar). Their best-characterized biological role is to silence Hox genes during development in organisms ranging from flies to mammals. Beyond Hox gene control, PcG proteins have widespread roles in silencing dozens of developmental decision makers, including critical transcription factors and signaling components in numerous cellular contexts and lineages. Among these many roles, PcG proteins are centrally deployed in the regulatory circuitry that maintains embryonic stem cells (ESCs), and they are also implicated in cancer epigenetics. PcG proteins provide a premier model for determining mechanisms of chromatin silencing. Two main PcG complexes have been defined and intensively studied, with discrete biochemical functions assigned to each (Simon and Kingston, 2009Simon J.A. Kingston R.E. Nat. Rev. Mol. Cell Biol. 2009; 10: 697-708Crossref PubMed Google Scholar). Polycomb repressive complex 2 (PRC2) has histone methyltransferase activity that modifies histone H3 on K27, and members of the PRC1 family of complexes can ubiquitylate histone H2A on K119. Although much attention has been devoted to these enzymatic functions and their outputs, it is not yet clear precisely how these chromatin marks help execute PcG silencing. There is strong evidence that PcG complexes also exert biochemical functions beyond deposition of histone tail modifications. One such potential function, chromatin compaction, has been demonstrated in vitro using discrete versions of either PRC1 or PRC2 (Francis et al., 2004Francis N.J. Kingston R.E. Woodcock C.L. Science. 2004; 306: 1574-1577Crossref PubMed Scopus (578) Google Scholar, Margueron et al., 2008Margueron R. Li G. Sarma K. Blais A. Zavadil J. Woodcock C.L. Dynlacht B.D. Reinberg D. Mol. Cell. 2008; 32: 503-518Abstract Full Text Full Text PDF PubMed Scopus (545) Google Scholar). In these studies, purified PcG complexes were incubated with nucleosome arrays, and the resulting PcG-chromatin complexes, viewed by electron microscopy, appear condensed with multiple nucleosomes collapsed into knot-like structures. This demonstrates the capacity of PcG complexes to bind and compact polynucleosomes, but leaves open the question of chromatin compaction at target loci in vivo. Here, Eskeland et al., 2010Eskeland R. Leeb M. Grimes G.R. Kress C. Boyle S. Sproul D. Gilbert N. Fan Y. Skoultchi A.I. Wutz A. Bickmore W.A. Mol. Cell. 2010; 38 (this issue): 452-464Abstract Full Text Full Text PDF PubMed Scopus (380) Google Scholar provide important new evidence for in vivo compaction, using mouse Hox loci as targets for analysis. Although prior studies correlate compacted chromatin with silent Hox genes, the current work advances significantly further by revealing contributions of individual PcG components to compaction. Eskeland et al., 2010Eskeland R. Leeb M. Grimes G.R. Kress C. Boyle S. Sproul D. Gilbert N. Fan Y. Skoultchi A.I. Wutz A. Bickmore W.A. Mol. Cell. 2010; 38 (this issue): 452-464Abstract Full Text Full Text PDF PubMed Scopus (380) Google Scholar use two-color fluorescence in situ hybridization (FISH) to track physical separation of DNA sequence pairs located 80–100 kb apart within the HoxB and HoxD loci in mouse ESCs. In this assay, the interprobe distances provide a measure of in vivo chromatin condensation. Initial tests establish that robust decompaction occurs at Hox loci, but not at control loci, upon treatment with retinoic acid, a differentiation stimulus that activates Hox genes. Key subsequent assays show that loss of either PRC2 (in Eed−/− cells) or PRC1 (Ring1B−/− cells) also causes substantial Hox decompaction, along with desilencing. The fact that loss of Ring1B triggers decompaction, despite maintaining normal H3K27me3 levels at Hox loci, reveals that K27 methylation is insufficient to produce the compacted state. Instead, the authors suggest that the main role of PRC2-mediated H3K27me3 is to first create a favorable landing pad to recruit or retain PRC1 at Hox targets. These results imply that compaction at Hox loci is more likely a consequence of PRC1 rather than PRC2. These findings parallel in vitro compaction of polynucleosomes by isolated PRC1, even with the histone tails removed (Francis et al., 2004Francis N.J. Kingston R.E. Woodcock C.L. Science. 2004; 306: 1574-1577Crossref PubMed Scopus (578) Google Scholar). For naysayers convinced that altered compaction is merely a secondary consequence of altered transcription status, the authors offer results with Ring1+/− heterozygous cells, which display some decompaction without significant changes in Hox expression. The most unexpected results emerge from rescue experiments where different flavors of the PRC1 subunit, Ring1B, are resupplied to Ring1B−/− cells. Here, the authors deploy a Ring1B missense mutant, I53A, rendered unable to ubiquitylate histone H2A due to active site disruption. Strikingly, they find that both wild-type and catalytically inactive Ring1B can restore compaction and silencing at Hox loci. This key result suggests that Ring1B enzymatic function, H2AK119 ubiquitylation, is dispensable for PRC1-mediated Hox compaction and not central to the silencing mechanism (see Figure 1). This contrasts with a previous study attributing Ring1B silencing to a role for H2A ubiquitylation in blocking transcription elongation (Stock et al., 2007Stock J.K. Giadrossi S. Casanova M. Brookes E. Vidal M. Koseki H. Brockdorff N. Fisher A.G. Pombo A. Nat. Cell Biol. 2007; 9: 1428-1435Crossref PubMed Scopus (494) Google Scholar). This study used Ring1B knockout rather than surgical removal of Ring1B enzymatic function. Importantly, Eskeland et al., 2010Eskeland R. Leeb M. Grimes G.R. Kress C. Boyle S. Sproul D. Gilbert N. Fan Y. Skoultchi A.I. Wutz A. Bickmore W.A. Mol. Cell. 2010; 38 (this issue): 452-464Abstract Full Text Full Text PDF PubMed Scopus (380) Google Scholar show, via coimmunoprecipitations, that their catalytically dead Ring1B retains normal association with PRC1 partner subunits, supporting the interpretation that an intact PRC1 complex lacking ubiquitin ligase activity can still compact chromatin. Given these results, the case of a distinct catalytically inactive missense allele of the Drosophila Ring1B homolog (Wang et al., 2004Wang H. Wang L. Erdjument-Bromage H. Vidal M. Tempst P. Jones R.S. Zhang Y. Nature. 2004; 431: 873-878Crossref PubMed Scopus (1163) Google Scholar), which is defective in Hox gene silencing, presents a puzzle that merits further study. The idea that PcG complexes may compact local chromatin has a long and controversial history. Indeed, an extension of this idea, that PcG chromatin organization might restrict access of the transcription machinery (Paro, 1990Paro R. Trends Genet. 1990; 6: 416-421Abstract Full Text PDF PubMed Scopus (315) Google Scholar), predates the discovery of PRC1 and PRC2 by a decade. However, PcG chromatin accessibility has proven difficult to definitively assess. One of the more extensive efforts tracked access of heterologous DNA-binding proteins to sites engineered directly into a fly Hox locus (Fitzgerald and Bender, 2001Fitzgerald D.P. Bender W. Mol. Cell. Biol. 2001; 21: 6585-6597Crossref PubMed Scopus (56) Google Scholar), which revealed reduced accessibility of PcG-silenced chromatin, compared to control genomic locations, but the block was not absolute. Subsequent studies detecting basal transcription factors and RNA polymerase II bound at PcG-silenced targets (Dellino et al., 2004Dellino G.I. Schwartz Y.B. Farkas G. McCabe D. Elgin S.C. Pirrotta V. Mol. Cell. 2004; 13: 887-893Abstract Full Text Full Text PDF PubMed Scopus (212) Google Scholar, Stock et al., 2007Stock J.K. Giadrossi S. Casanova M. Brookes E. Vidal M. Koseki H. Brockdorff N. Fisher A.G. Pombo A. Nat. Cell Biol. 2007; 9: 1428-1435Crossref PubMed Scopus (494) Google Scholar) have largely refuted the idea of an impervious PcG block. However, compacted structure, as observed by Eskeland et al., 2010Eskeland R. Leeb M. Grimes G.R. Kress C. Boyle S. Sproul D. Gilbert N. Fan Y. Skoultchi A.I. Wutz A. Bickmore W.A. Mol. Cell. 2010; 38 (this issue): 452-464Abstract Full Text Full Text PDF PubMed Scopus (380) Google Scholar, can still play a key role distinct from wholesale chromatin lockdown. The accessibility of regulatory surfaces (on DNA or histones) within compacted chromatin will depend upon the precise molecular geometry of the compacted state, which is currently not known. Furthermore, factor access to PcG-compacted structures, such as those visualized in vitro (Francis et al., 2004Francis N.J. Kingston R.E. Woodcock C.L. Science. 2004; 306: 1574-1577Crossref PubMed Scopus (578) Google Scholar, Margueron et al., 2008Margueron R. Li G. Sarma K. Blais A. Zavadil J. Woodcock C.L. Dynlacht B.D. Reinberg D. Mol. Cell. 2008; 32: 503-518Abstract Full Text Full Text PDF PubMed Scopus (545) Google Scholar), will depend upon locations and dynamics of target surfaces in vivo. Relevant to this, a fluorescence recovery after photobleaching (FRAP) study showed that PRC1 subunits exchange rapidly, on the order of a few minutes, in living cells (Ficz et al., 2005Ficz G. Heintzmann R. Arndt-Jovin D.J. Development. 2005; 132: 3963-3976Crossref PubMed Scopus (106) Google Scholar). While this result argues against a static role for PRC1 in organizing PcG-silenced chromatin, it does not really address whether compaction operates at PcG targets. Compacted chromatin that retains flexibility to respond to signaling inputs such as retinoic acid (Eskeland et al., 2010Eskeland R. Leeb M. Grimes G.R. Kress C. Boyle S. Sproul D. Gilbert N. Fan Y. Skoultchi A.I. Wutz A. Bickmore W.A. Mol. Cell. 2010; 38 (this issue): 452-464Abstract Full Text Full Text PDF PubMed Scopus (380) Google Scholar) is entirely consistent with PRC1 subunits in dynamic equilibrium in vivo. Similarly rapid exchange kinetics apply to heterochromatin protein 1 (HP1), an original poster child in models for stably silenced chromatin. Together, these findings support a general view of compacted chromatin structure built using highly dynamic components. Although we have useful portraits of individual PcG family members and what they do, we cannot yet view the full landscape of PcG-silenced chromatin. The current work (Eskeland et al., 2010Eskeland R. Leeb M. Grimes G.R. Kress C. Boyle S. Sproul D. Gilbert N. Fan Y. Skoultchi A.I. Wutz A. Bickmore W.A. Mol. Cell. 2010; 38 (this issue): 452-464Abstract Full Text Full Text PDF PubMed Scopus (380) Google Scholar) expands the gallery, though, by refocusing attention on PcG compaction and highlighting functions beyond histone tail modifications. It will be important to assess PcG compaction at non-Hox genes, as Hox loci have specialized arrangements and PcG mechanisms may not be identical at all targets. It will also be key to determine how PcG compaction might impact the transcription cycle. How could the polynucleosomal template be reconfigured by PcG complexes in a way that impedes transcription and preserves dynamic flexibility? Mechanistic answers might well emerge from new in vitro approaches for functional analysis of compacted chromatin (Li et al., 2010Li G. Margueron R. Hu G. Stokes D. Wang Y.H. Reinberg D. Mol. Cell. 2010; 38: 41-53Abstract Full Text Full Text PDF PubMed Scopus (63) Google Scholar). As emphasized by Eskeland et al., 2010Eskeland R. Leeb M. Grimes G.R. Kress C. Boyle S. Sproul D. Gilbert N. Fan Y. Skoultchi A.I. Wutz A. Bickmore W.A. Mol. Cell. 2010; 38 (this issue): 452-464Abstract Full Text Full Text PDF PubMed Scopus (380) Google Scholar, there is likely yet more to discover about chromatin polyfunctions of Polycomb complexes. Ring1B Compacts Chromatin Structure and Represses Gene Expression Independent of Histone UbiquitinationEskeland et al.Molecular CellMay 14, 2010In BriefHow polycomb group proteins repress gene expression in vivo is not known. While histone-modifying activities of the polycomb repressive complexes (PRCs) have been studied extensively, in vitro data have suggested a direct activity of the PRC1 complex in compacting chromatin. Here, we investigate higher-order chromatin compaction of polycomb targets in vivo. We show that PRCs are required to maintain a compact chromatin state at Hox loci in embryonic stem cells (ESCs). There is specific decompaction in the absence of PRC2 or PRC1. Full-Text PDF Open Archive" @default.
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• W2071184971 date "2010-05-01" @default.
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• W2071184971 title "Chromatin Compaction at Hox Loci: A Polycomb Tale beyond Histone Tails" @default.
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