Coordinated Chromatin Control: Structural and Functional Linkage of DNA and Histone Methylation

Abstract

One of the most fundamental questions in the control of gene expression in mammals is how epigenetic methylation patterns of DNA and histones are established, erased, and recognized. This central process in controlling metazoan gene expression includes coordinated covalent modifications of DNA and its associated histones. This review focuses on recent developments in characterizing the functional links between the methylation status of the DNA and of two particularly important histone marks. Mammalian DNA methylation is intricately connected to the presence of unmodified lysine 4 and methylated lysine 9 residues in histone H3. An interconnected network of methyltransferases, demethylases, and accessory proteins is responsible for changing or maintaining the modification status of specific regions of chromatin. The structural and functional interactions among members of this network are critical to processes that include imprinting and differentiation, dysregulation of which is associated with disorders ranging from inflammation to cancer.

Investigation of the Molecular Origins of Protein-arginine Methyltransferase I (PRMT1) Product Specificity Reveals a Role for Two Conserved Methionine Residues

“…In yeast, MMA present in histone H3 at Arg-2 correlates to active transcription, whereas the ADMA state contributes to transcriptional repression (7). In contrast to the idea that MMA is simply an intermediate for ADMA generation, the current data point to a bona fide signaling role for MMA residues in much the same way that mono-, di-, and trimethylation of lysine residues differentially affect signaling (8,9). A key to understanding the biological function of the PRMTs is to understand how product specificity may be regulated, in terms of governing which arginyl residues are modified and which state of methylation is achieved.…”

Epigenetic Mechanisms in Inflammation

“…These post-translational modifications (methylation of lysines and arginines, acetylation, phosphorylation, ubiquitination, SUMOylation, and ADP-ribosylation) occur most frequently at the N-terminal tails of the core histones (Fuchs et al, 2006). Acetylation of histones is associated with an "open" chromatin conformation that facilitates transcription (Campos and Reinberg, 2009;Cheng and Blumenthal, 2010). The acetylated N termini protruding from the nucleosome core provide reduced affinity for the DNA, allowing the chromatin to adopt a more relaxed structure for the recruitment of the basic transcription machinery.…”

“…However, PRC2 may use different recruitment mechanisms to target different downstream genes (Peng et al, 2009;Shen et al, 2009;Landeira et al, 2010;Li et al, 2010;Pasini et al, 2010). PRC2 forms a stable complex with the transcriptional repressor JARID2, a member of the Jumonji C (JmjC) and ARID domain protein family (Cheng and Blumenthal, 2010). JARID2 binds to the PcG-responsive sites through the DNAbinding domain ARID (Fig.…”

Histone tails regulate DNA methylation by allosterically activating de novo methyltransferase

“…A fundamental question concerns how a specific sequence is selectively methylated by the de novo enzymes in cells. Evidence for cross-talk between DNA methylation and histone modification has been found in various contexts of transcriptional regulation and chromatin functions [4][5][6][7][8]. In the filamentous fungus Neurospora crassa, either the replacement of histone H3 lysine 9 (H3K9) with other amino acids or deletion of the sole H3K9 methyltransferase DIM5 results in the loss of DNA methylation [9].…”

“…However, the exact mechanism for the transformation of a chromatin modification status into DNA methylation is left unexplored. The current model of DNA methylation [7,17] underscores the recruitment of Dnmt3 enzymes to genomic targets via direct or indirect binding to histone tails [13][14][15]18]. While this model assumes that the histone tail with a specific modification state specifies a docking site for Dnmts as for many other chromatin binding/modifying proteins, it does not consider the possibility that the enzymatic activity of Dnmts might be regulated by histone tails and their modification.…”