1. Methylation of Lysine 4 on Histone H3: Intricacy of Writing and Reading a Single Epigenetic Mark 
Alexander J. Ruthenburg, C. David Allis, Joanna Wysocka 
Molecular Cell 
Volume 25, Issue 1, Pages (January 2007)
DOI: /j.molcel
Copyright © 2007 Elsevier Inc. Terms and Conditions

2. Figure 1 Writing the H3K4 Methylation Mark
(A) Schematic representation of the domain architecture of known H3K4 histone methyltransferases (HMTs). The H3K4 HMTs are represented by two groups: proteins containing SET domains related to the SET domain of yeast Set1 and Drosophila Trx (MLL family), or those unrelated yet able to methylate H3 at K4 (other H3K4 methyltransferases). The six members of the MLL family likely arose through genome duplication during vertebrate evolution, with MLL1/MLL2, MLL3/MLL4, and SET1A/SET1B having common ancestors. The domain architecture was analyzed with SMART.
(B) Schematic representation of the interactions between MLL complex components. MLL-family HMTs associate with the core complex containing RbBP5, WDR5, and ASH2. The core complex cooperates with the catalytic SET domain to methylate H3 at K4, whereas other regions of the MLL protein are involved in association with other protein partners and in recruitment of the MLL complex to the target genes. WDR5 plays a role in substrate recognition and presentation, with preferential, but not exclusive, binding to the H3K4me2 substrate.
(C) Mechanisms of H3K4 methyltransferase recruitment to the target genes. Although precise mechanisms of recruitment remain to be determined, the existing literature suggests that H3K4 methyltransferases are recruited to and/or stabilized on chromatin by a combination of mechanisms involving association with site-specific transcription factors (a), basal machinery (b), histone modification recognition (c), and specific RNAs (d). For references, see text.
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3. Figure 2 Reading the H3K4 Methylation Mark
(A) Schematic representation of the domain architecture of known readers of H3K4 methylation. The structural motifs involved in the H3K4 methyl recognition are highlighted. Preferentially recognized methyl state and association with multiprotein complexes are indicated. The domain architecture was analyzed with SMART.
(B) Combinatorial reading of histone modifications. Many chromatin-associated protein complexes contain multiple histone modification recognition modules. These modules can be present within a single protein, as exemplified by BPTF of the NURF complex, whose H3K4 binding PHD finger is adjacent to the bromodomain (a), or in multiple components of the complex, as exemplified by the NuA4 complex, containing PHD-finger protein Yng2 recognizing H3K4 methyl, and chromodomain protein Eaf3, recognizing H3K36 methyl (b).
(C) Distinction between recruitment and stabilization. Methylated histone recognition is likely not a primary targeting determinant for chromatin-associated complexes, instead sequence-specific recruitment mechanisms mediated by the site-specific transcription factors or RNAs may be favored. Once recruited, however, stabilization through specific methyl-lysine recognition might allow for efficient association of the complex with chromatin over a larger domain than dictated by the presence of the transcription factor or RNA on the regulatory element. This idea is exemplified here with NURF, which is recruited to chromatin by the sequence-specific transcription factors (including the GAGA factor) and stabilized through H3K4 methyl-lysine recognition.
(D) Association of methyl-lysine reader with chromatin in response to a cellular signaling event. PHD fingers of ING proteins can bind the phosphatididylinositol phosphate (PtdInsP) signaling molecules independently of their association with the methylated H3K4. An increase in the nuclear pool of PtdInsP upon DNA damage is important for ING2 recruitment to chromatin and likely lies upstream from the H3K4 methyl recognition. For references, see text.
Molecular Cell  , 15-30DOI: ( /j.molcel )
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4. Figure 3
Molecular Recognition of H3K4 Methylation and the Royal Superfamily of Effectors
(A) An aromatic cage as exemplified by the JMJD2A second hybrid tudor domain. Cage resides are colored in blue, the remainder of the protein is depicted in gray, and the histone H3K4me3 peptide is colored in green.
(B) The cation-π effect. A scheme of the permanent quadrupole moment of an aromatic residue—the quadrupole can to first approximation be thought of as two dipoles in opposition that distribute partial charge (δ) in the manner shown. The ideal geometry for cation-π interactions places a given cation above the center of an aromatic moiety within van der Waals hard packing distance.
(C) The royal superfamily of folds are colored with homologous β barrel motifs in blue, the Cα's of conserved aromatic-cage residues are depicted as purple spheres, divergent structural elements are colored in gray, and histone H3 peptides are depicted in green. An additional β strand or helix occupies one face of the usually four-stranded core—these moieties are colored orange. Clockwise from the upper left structure is the MOF chromo barrel (PDB 2BUD), the CHD1 double chromodomain (PDB 2B2W), the SMN tudor domain (PDB 1MHN), JMJD2A double tudor domain (PDB 2B2W), the 53BP1 tandem tudor (PDB 1XNI), the DNMT3b PWWP domain (PDB 1KHC), the malignant brain tumor MBT domain (PDB 1OZ2, only one of the three MBT repeats is shown for clarity), and HP1 chromodomain (PDB 1KNE) are shown to illustrate structural homology and the known or putative histone interaction surfaces (depicted as wireframe cartoon). Note that the chromo barrel structure depicted is a composite of the MOF structure with the positions of aromatic residues that are only conserved in the MSL3 subfamily of the fold for which there is no structural data available. It has been predicted that MSL3-like chromo-barrel domains may be able to bind peptide in the manner displayed (Nielsen et al., 2005).
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5. Figure 4
PHD Fingers as H3K4 Methylation-Sensitive Effectors and Related Folds
(A) Set of PHD-like interleaved dual zinc-finger folds. The FYVE structural relative is quite similar to the PHD finger, and importantly, an unobstructed β sheet edge exists that, in principle, could permit the same peptide binding mode as observed in the PHD-finger structures (gray outline of a β strand). This is not the case for the RING fingers that have been structurally elucidated—an additional β strand as well as a characteristic helix obstruct PHD-finger-like peptide association. Structurally homologous regions of these folds are displayed in blue, internal divergent regions in yellow, terminal divergent regions in gray, histone H3 peptide in green, and zinc ions as lavender spheres.
(B) The ING2 PHD finger is colored according to the structure-based sequence alignment in (C). Note that a small side chain (A or G) is the first residue of the R2-interaction motif in all known H3K4 methyl-specific PHD fingers—apparently to permit the excursion of the R2 side chain into the guanidinium recognition pocket. The alignment is restricted to those PHD fingers that have been structurally or biochemically characterized as H3K4me3 binding effectors as well those predicted to bind methyl-lysine as assessed from structure-based alignment (3DCoffee).
Molecular Cell  , 15-30DOI: ( /j.molcel )
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6. Figure 5 Multivalency and Chromatin Modification Complexes
Simplified thermodynamic treatment of two effector modules that bind immobile polymeric substrate independently (left panels) or are linked in a rigidly preorganized complex (right panels). In the event of coincident binding, the conformational and rotational entropy terms (subsumed within the overall entropy change, ΔSi) would be prepaid by the inflexibility of the linker.
Molecular Cell  , 15-30DOI: ( /j.molcel )
Copyright © 2007 Elsevier Inc. Terms and Conditions