Chromatin dynamics: interplay between remodeling enzymes and histone modifications

Abstract

Chromatin dynamics play an essential role in regulating the accessibility of genomic DNA for a variety of nuclear processes, including gene transcription and DNA repair. The posttranslational modification of the core histones and the action of ATP-dependent chromatin remodeling enzymes represent two primary mechanisms by which chromatin dynamics are controlled and linked to nuclear events. Although there are examples in which a histone modification or a remodeling enzyme may be sufficient to drive a chromatin transition, these mechanisms typically work in concert to integrate regulatory inputs, leading to a coordinated alteration in chromatin structure and function. Indeed, site-specific histone modifications can facilitate the recruitment of chromatin remodeling enzymes to particular genomic regions, or they can regulate the efficiency or the outcome of a chromatin remodeling reaction. Conversely, chromatin remodeling enzymes can also influence, and sometimes directly modulate, the modification state of histones. These functional interactions are generally complex, frequently transient, and often require the association of myriad additional factors. This article is part of a Special Issue entitled: Molecular mechanisms of histone modification function.

Keywords: Chromatin dynamics; Chromatin remodeling; Histone modifications.

Figure 1. Chromatin remodeling enzymes have specific domains that bind histone modifications

(a) Bromodomains bind acetylated lysines. The bromodomain of Gcn5 bound to an H4 tail peptide acetylated at K16 (PDB: #1E6I). (b) Chromodomains bind methylated lysines. The chromodomain of HP1 protein Swi6 bound to an H3 tail peptide methylated at K9 (PDB: #1KNA). (c) PHD fingers bind methylated lysines. The PHD finger domain of ING2 bound to an H3 tail peptide methylated at K4 (PDB: #2G6Q).

Figure 2. Chromatin remodeling enzymes can modify histone marks

(a) Tip60 binds H3-K9me nucleosomes and acetylates H4 tails. (b) The NuRD complex binds H3-K9me nucleosomes and deacetylates them. (c) SMARCAD1 deacetylates newly-deposited nucleosomes during replication via association with subunits HDAC1 and HDAC2. (d) The Uch37 subunit of human INO80 has been recognized to posses DUB activity that may allow INO80 to target nucleosomes for deubiquitylation.

Figure 3. Histone modifications can regulate chromatin remodeling activity

(a) ISWI contains a regulatory region homologous to the H4 tail, called AutoN, which binds the ATPase domain and inhibits activity. When ISWI binds the H4 tail, AutoN is displaced and ATPase activity resumes. However, H4 tails acetylated at K16 do not displace AutoN, and consequently inhibit ISWI function. (b) SWR-C exchanges H2A/H2B dimers for dimers containing H2A.Z. However, the presence of H3 K56ac alters the substrate specificity of SWR-C, allowing it to exchange dimers in both directions.

Figure 4. Histone modifications and chromatin remodeling enzymes exhibit complex interactions

(a) At DSB’s, γ-H2A.X recruits Gcn5 to nucleosomes, where it acetylates the H3 tail and consequently favors BAF binding. BAF then remodels nearby nucleosomes, leading to spreading of the γ-H2A.X mark and continuation of the cycle. (b) H2B ubiquitylation at a DSB recruits Set1, which methylates H3 K4, leading to binding by the ACF subunit SNF2H. The remodeling enzyme then remodels nearby nucleosomes in a way that favors spreading of the ubiquitin mark. (c) H3-K36me nucleosomes are targeted by Rpd3S for deacetylation in gene bodies. ISWI1b and CHD1 space methylated nucleosomes preferentially for Rpd3S binding to two nucleosomes at once.