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- 1. EFECTOS EPIGENÉTICOS DE LAS PROTEÍNAS DEL COMPLEJO POLYCOMB EN EL REMODELAMIENTO DE LA CROMATINA
- 3. Introducción
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- Figure 1 | How Polycomb group complexes regulate a homeotic gene. The correct domain of expression of the Ultrabithorax ( Ubx ) gene is posterior to parasegment 6 (indicated by an arrowhead). Ubx regulation is recapitulated by a series of reporter constructs, using the Ubx promoter and different combinations of the Ubx embryonic enhancer, Polycomb response element (PRE) and imaginal disc enhancer. The expression pattern that is produced by the different combinations is shown as blue-coloured regions of the early embryo, later embryo or the imaginal disc precursors of adult head, wing or haltere. The early enhancer initially produces the correct pattern of expression, confined to the posterior half of the embryo (posterior to parasegment 6). Shortly after, however, the early repressors in the anterior region disappear and the reporter gene is expressed in all segments. If the PRE is added, repression is maintained in the anterior region. Imaginal disc enhancers are active only at later stages in the head, wing and haltere discs. If combined with the PRE, they remain in the silent state that is established in the embryo. However, when the three elements are combined, the early enhancer sets the early pattern, the PRE maintains the repression anterior to parasegment 6, and the imaginal disc enhancer now remains active posterior to parasegment 6; that is, in the haltere, but not in the wing or head.
- Figure 2: The mechanism for gene-expression suppression and promotion by the Polycomb group and the trithorax group. Regarding the suppression and promotion of gene expression, the following is hypothesized. The Polycomb group comprises two major components: PRC1 and PRC2. First, PRC2 binds to the target region to methylate a particular site of histone. The PCR1 component is then attracted there to suppress gene expression. If the Polycomb group becomes less dominant, the trithorax group (TrxG) soon comes to promote gene expression.
- SWI/SNF (SWItch/Sucrose NonFermentable) [1] [2] is a yeast nucleosome remodeling complex composed of several proteins - products of the SWI and SNF genes ( SWI1 , SWI2 / SNF2 , SWI3 , SWI5 , SWI6 ) as well as several other polypeptides. [3] It possesses a DNA-stimulated ATPase activity and can destabilize histone -DNA interactions in reconstituted nucleosomes in an ATP -dependent manner, though the exact nature of this structural change is unknown.
- Figure 2 | Prc2 composition in flies and humans. a | The four core subunits of Polycomb repressive complex 2 (PRC2), as purified from Drosophila melanogaster embryos. The protein contacts illustrated here reflect experimentally determined subunit interactions74–77. The catalytic subunit, Enhancer of Zeste (E(Z)), contains a SET domain that houses the enzyme active site for histone H3 Lys27 (H3K27) methylation. The three non-catalytic subunits are Suppressor of Zeste 12 (SU(Z)12), Extra Sex combs (ESC) and nucleosome remodelling factor 55 (NURF55; also known as p55 and CAF1). In addition to E(Z), both SU(Z)12 and ESC are crucial for histone methyltransferase activity. The arrow denotes the interaction of PRC2 with another Polycomb group protein, Polycomb-like (PCL). Although not a core subunit, PCL association with PRC2 can influence PRC2 function91–94. The dotted line denotes possible substitution for ESC of an alternative PRC2 subunit, ESC-like (ESCL), which is generated from multiple gene copies. b | The four core subunits of PRC2, as purified from human cells. The catalytic subunit, E(Z) homologue 2 (EZH2), contains a SET domain that houses the active site for histone H3K27 methylation. The three non-catalytic subunits are SU(Z)12, embryonic ectoderm development (EED) and retinoblastoma-binding protein p48 (RBAP48; also known as RBBP4). In addition to EZH2, both SU(Z)12 and EED are crucial for histone methyltransferase activity. The arrow denotes the interaction of PRC2 with another PcG protein, PHF1 (also known as PCL1). Although not a core subunit, PHF1 association with PRC2 can influence its function91–94. The dotted lines denote possible substitution of alternative PRC2 subunits generated from multiple gene copies (RBAP46 (also known as RBBP7), EZH1, MTF2 (also known as PCL2) and PHF19 (also known as PCL3)) or as protein variants from a single gene (EED variants).
- Methylation of histone H3 by the PRE complexes. a | The model depicts DNA-binding proteins, of which only pleiohomeotic (PHO) and GAGA factor (GAF) are shown, binding to the Polycomb response element (PRE), which is shown free of nucleosomes (grey spheres), possibly with the help of a chromatin remodelling complex, and cooperatively recruiting the PRC1 and PRC2 complexes. b | The PRE-bound complexes methylate flanking nucleosomes (indicated by red pinballs on the nucleosomes) on either side of the PRE. c | The methylation domain is extended by looping of the PRE-bound complexes to contact nucleosomes over a broad region. The looping is mediated by interactions of the PC chromodomain and possibly other methyl-binding domains, such as PHD fingers, MBD, Tudor and SET domains in other PcG proteins, creating and maintaining a broad methylation domain. The PRE also constitutively binds Trithorax (TRX), which would be carried along in the looping contacts and could, in principle, also deposit the histone H3 methylation of lysine 4 (H3K4) mark
- Figure 1 | recruitment of Pcg complexes to target genes. a | In Drosophila melanogaster , the DNA-binding protein Pleiohomeotic (PHO) and its relative PHO-like (PHOL) have central roles in recruiting Polycomb group (PcG) complexes to Polycomb response elements (PREs). PHO exists in a repressive complex called PHO-RC50. Dotted lines represent physical interactions that have been described between PHO and subunits of Polycomb repressive complex 2 (PRC2)49 and PRC1 (REF. 113), which could help to target these complexes. Several other DNA-binding proteins, including GAGA factor (GAF), have been implicated in functioning at fly PREs but evidence for their roles in PcG recruitment is less conclusive than for PHO42. b | In mammals, no central recruiter proteins or DNA elements have yet been identified. Candidate proteins include OCT4 (also known as POU5F1)21 and yin and yang 1 (YY1)57, and CpG islands are commonly associated with PcG target genes in embryonic stem cells55. Non-coding RNAs (ncRNAs) can interact with PRC2 and have been suggested to be PcG recruiters at selected target loci59,61,62. X represents additional unknown elements that might contribute to PREs in D. melanogaster and mammals
- Figure 2 | turning off pluripotency genes. In embryonic stem cells, pluripotency genes such as Oct3/4 and Nanog have unmethylated CpG islands (light purple circles) and are packaged with acetylated (Ac) histone H3 and H4 and methylated (Me) lysine 4 of histone H3 (H3K4). With the onset of differentiation the SET domain-containing histone methyltransferase G9a is recruited, together with a histone deacetylase (HDAC), and this causes deacetylation of local histones. In addition, H3K4 is demethylated, but the enzymatic machinery responsible for this has not yet been identified. In the next step, G9a catalyses the methylation of H3K9, and this modification serves as a binding site for the chromodomain protein heterochromatin protein 1 (HP1), thus generating a form of local heterochromatin. Finally, G9a recruits the methylases DNMT3A and DNMT3B, which mediate de novo methylation (dark purple circles) of the underlying DNA21,22
- Figure 3 | Potential roles for H3K27me3 in Pcg function. a | The possible role of trimethylated histone H3 on Lys27 (H3K27me3) in Polycomb repressive complex 1 (PRC1) targeting. In initial steps, the Pleiohomeotic repressive complex (PHO-RC) recognizes Polycomb response elements (PREs) and recruits PRC2, which methylates local nucleosomes. Because the PRE is probably devoid of nucleosomes31, PRC2 arrival would be expected to methylate flanking nucleosomes. The accumulated local H3K27me3 could help attract, bind and stabilize PRC1 through the Polycomb chromodomain. PRC1 recruitment to the PRE region could also involve direct protein contacts with PHO-RC and/or PRC2. b | The potential role of H3K27me3 in chromatin looping. PRC1, anchored at the PRE, could interact with H3K27me3 to stabilize contact with the gene31,42. The resulting intralocus loop would juxtapose the Polycomb group complexes and the transcribed region, where PRC2 could further spread H3K27 methylation and PRC1 could ubiquitylate histone H2A, compact local nucleosomes and/or impede RNA polymerase (FIG. 5). Additional possible roles for H3K27me3, including binding to other complexes, altering nucleosome–nucleosome interactions and influencing elongation factors, are not shown
- Examples of post-translational modulation of Polycomb group and associated proteins . (a) Simplified model of Polycomb Group (PcG)-mediated repression. The histone methyltransferase EZH2 trimethylates histone H3 at lysine 27, this mark is recognized by chromobox homolog (CBX) proteins via the chromodomain. RNF2/RING1 homologs are E3 ubiquitin ligases for H2A; RYBP binds H2AK119Ub1. Combined, these activities induce/maintain transcriptional repression. Gray boxes depict Polycomb Repressive Complex (PRC)-associated, epigenetically relevant enzymatic activities.