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.

Figure 1

Diagram of interactions that regulate DNA methylation and associated histone H3 modifications. The actions of proteins and arrows are indicated by color: green for activities associated with an increased level of gene expression and red for those tending to decrease the level of expression. Binding interactions are indicated by dashed lines. The “m” in a red circle indicates one or more methyl groups inDNA(5mC)orproteinlysines (Km). Fordetails, seethetext.

Figure 2

Cross talk between Jumonji and PHD/Tudor domains within the same polypeptide. (A) Schematic representations of PHF8 and KIAA1718. These two proteins bind methylated H3K4 via their PHD domains and demethylate H3K9 (and H3K27) via their Jumonji domains; however, methylated H3K4 stimulates the K9 activity of PHF8 and depresses that of KIAA1718 (68). Superimposition of PHF8 (colored) and KIAA1718 (gray) via their respective Jumonji domains reveals that the PHF8 PHD domain adopts a bent conformation relative to the Jumonji domain in the presence of H3 substrate, while the PHD and Jumonji domains of KIAA1718 adopt an extended conformation (in its apo structure) (68). (B) Schematic representation of Lid2 H3K4 demethylase of S. pombe (65) [SMCX/JARID1C (72)]. (C) Schematic representation of JMJD2A (73-77). This protein demethylates H3K9me3/2 (and H3K36me3/2) via its Jumonji domain, while its Tudor domain binds K4me3 on H3 and K20me3 onH4. The opposing red triangles indicate each of the two demethylase activities might correlate with one of the recognized methyl marks.

Figure 3

Model for interaction between the Dnmt3a-3L tetramer and a nucleosome. A nucleosome is shown (top), docked to a Dnmt3L-3a-3a-3L tetramer (3a colored green and 3L gray). The position of a peptide derived from the sequence of the histone H3 amino terminus (purple) is shown, taken from a cocrystal structure with this peptide bound to Dnmt3L (59). By wrapping the tetramer around the nucleosome, as shown, the two Dnmt3L molecules could bind both histone tails from one nucleosome. The amino-proximal portion ofDnmt3a is labeledN(for the N-terminal domain), and the PWWPandADDdomains are indicated. By analogy toDnmt3L, the ADDdomain ofDnmt3a [ProteinDataBank entry 3A1B (60)] might interact with histone tails from neighboring nucleosomes (bottom).

Figure 4

Hypothetical model of UHRF1/Dnmt1-mediated replication-coupled cross talk between DNA methylation and histone modifications. The existence of both silencingmark readers recognizing DNA (via the SRA) and histone (via the Tudor and/or PHD domain) facilitates the idea of maintenance and conversion of epigenetic silencing marks on both DNA and histone modifications.