The role of the nucleosome acidic patch in modulating higher order chromatin structure

Abstract

Higher order folding of chromatin fibre is mediated by interactions of the histone H4 N-terminal tail domains with neighbouring nucleosomes. Mechanistically, the H4 tails of one nucleosome bind to the acidic patch region on the surface of adjacent nucleosomes, causing fibre compaction. The functionality of the chromatin fibre can be modified by proteins that interact with the nucleosome. The co-structures of five different proteins with the nucleosome (LANA, IL-33, RCC1, Sir3 and HMGN2) recently have been examined by experimental and computational studies. Interestingly, each of these proteins displays steric, ionic and hydrogen bond complementarity with the acidic patch, and therefore will compete with each other for binding to the nucleosome. We first review the molecular details of each interface, focusing on the key non-covalent interactions that stabilize the protein -acidic patch interactions. We then propose a model in which binding of proteins to the nucleosome disrupts interaction of the H4 tail domains with the acidic patch, preventing the intrinsic chromatin folding pathway and leading to assembly of alternative higher order chromatin structures with unique biological functions.

Histone chaperone Anp32e removes H2A.Z from DNA double-strand breaks and promotes nucleosome reorganization and DNA repair

“…2A). This acidic domain is adjacent to (and partially overlaps with) the Anp32e interaction domain on H2A.Z (20,(27)(28)(29) (Fig. 2A).…”

“…Anp32e binding may therefore promote H4Ac by either displacing the H4 tail from the adjacent acidic domain or by removing H2A.Z and eliminating the entire H4 binding surface. To test this hypothesis, we used the LANA protein of Kaposi's sarcoma herpes virus (27). LANA protein binds tightly to the acidic patch (30,31), using the same acidic amino acids to which the H4 tail binds.…”

“…H2A.Z contains a specific binding site for Anp32e (20,21), which partially overlaps with the acidic domain to which the H4 tail binds (24)(25)(26)(27). Anp32e binding to H2A.Z may displace the H4 tail, promoting H4 acetylation.…”

Active chromatin and transcription play a key role in chromosome partitioning into topologically associating domains

“…In this case, nucleosomes of inactive chromatin would form various supra-nucleosomal structures due to interactions between positively charged histone tails of one nucleosome and the acidic patch of another nucleosome (Luger et al 1997;Schalch et al 2005;Sinha and Shogren-Knaak 2010). These interactions are thought to contribute to folding of nucleosomal arrays into secondary chromatin structures and self-association of arrays into higher-order tertiary structures (Kalashnikova et al 2013;Pepenella et al 2014), which collectively may result in formation of TADs. We propose that those differences in physical properties of nucleosomal arrays in active and inactive chromatin are sufficient to direct self-assembly of TADs separated by inter-TADs.…”

Synthetic Nucleosomes Reveal that GlcNAcylation Modulates Direct Interaction with the FACT Complex

“…The “acidic patch” is a negatively‐charged binding interface on the nucleosome surface 9. A number of proteins, such as LANA,10 IL‐33,11 RCC1,12 Sir3,13 HMGN2,14 RNF168,15 and RING1B/BMI1,15 as well as the H4 tail,1 are known to interact competitively with the “acidic patch” leading to remodeling of chromatin structure; we speculated that because of its proximity H2B‐Ser112 O ‐GlcNAcylation could directly modulate binding.…”