Histone Tail Conformations: A Fuzzy Affair with DNA

Abstract

The core histone tails are critical in chromatin structure and signaling. Studies over the past several decades have provided a wealth of information on the histone tails and their interaction with chromatin factors. However, the conformation of the histone tails in a chromatin relevant context has remained elusive. Only recently has enough evidence emerged to start to build a structural model of the tails in the context of nucleosomes and nucleosome arrays. Here, we review these studies and propose that the histone tails adopt a high-affinity fuzzy complex with DNA, characterized by robust but dynamic association. Furthermore, we discuss how these DNA-bound conformational ensembles promote distinct chromatin structure and signaling, and that their fuzzy nature is important in transitioning between functional states. Highlights Eukaryotic DNA is wrapped around histone proteins to form nucleosomes that fold into higher-order chromatin structures, and the local chromatin structure regulates all DNA-templated processes. All core histone proteins contain intrinsically disordered tail regions that protrude from the DNA-wrapped core and are known to be critical in chromatin regulation. Recent studies have revealed that the core histone tails adopt multiple conformations on the nucleosomal and linker DNA; these tail/DNA interactions are robust, but exchange quickly between multiple conformations consistent with a so-called fuzzy complex. Intra-versus inter-nucleosome contacts by the tails differentially contribute to the local chromatin state and thus regulation of DNA-templated processes. Histone post-translational modifications and chromatin-associated factors can modulate these fuzzy conformational ensembles and tail accessibility, indicating that the tail/DNA interactions are an important regulatory mechanism of chromatin.

Binding of regulatory proteins to nucleosomes is modulated by dynamic histone tails

“…The interactions between tails and DNA are transient, and switching between tail conformations occurs on the time scale from tens and hundreds of nanoseconds to several microseconds in the form of jittery motions, with the H2A C-terminal tail having the shortest residence time on DNA and H3 tail having the longest residence time. The emerging body of experimental evidence has pointed to the high level of conformational dynamics of histone tails, with the dynamic conformational transitions on the order of sub-microseconds 9 , 37 , 38 . This is consistent with our observed highly dynamic tail behavior from simulations.…”

“…Beyond the intra-nucleosomal interactions, tail–DNA interactions have long been indicated to play critical roles in inter-nucleosome interactions 37 , 48 . It has been shown that H3 and H4 tail–DNA interactions are important for compaction and oligomerization of nucleosome arrays 49 .…”

Is There a Histone Code for Cellular Quiescence?

“…For mammalian chromosomes, this tight packing results in a 10,000-fold reduction in length (Kornberg and Lorch, 2020). The DNA in chromatin forms complexes with histone proteins that assemble the DNA strands into nucleosomes in a structure that resembles "beads on a string" with the nucleosomes (beads) representing the basic repeating unit of chromatin (Cutter and Hayes, 2015;Zhou et al, 2019;Ghoneim et al, 2021). Each core nucleosome consists of ∼147 base pairs (bp) of DNA in a left-handed super-helical conformation wrapped around an octamer of histone proteins (Zhou et al, 2019).…”

“…The disordered N-terminal tails of all four histone proteins as well as the C-terminal tail of H2A protrude out from the nucleosome core and are sites of diverse post translational modifications (PTMs) or marks such as lysine and arginine methylation, lysine acetylation, and serine and threonine phosphorylation (Bannister and Kouzarides, 2011;Greer and Shi, 2012;Cutter and Hayes, 2015). These histone tails modulate charge, hydrophobicity, and steric access to chromatin (Ghoneim et al, 2021). Histone PTMs Allen et al, 2006 Fission yeast Cell culture Nitrogen-induced starvation; Glucose deprivation Hayashi et al, 2018;Zahedi et al, 2020 Human dermal fibroblasts Cell culture Serum-starvation; Contact-inhibition Evertts et al, 2013a;Mitra et al, 2018a Human lung fibroblasts Cell culture Mitogen withdrawal; Contact inhibition; Loss of adhesion are added and removed by enzymatic proteins referred to as "writers" and "erasers, " respectively (Soshnev et al, 2016;Hyun et al, 2017;Husmann and Gozani, 2019).…”

Proline residues impart a tripartite segmental behavior to the nucleosomal H3 histone tail in the unmodified and posttranslationally modified states

“…The DNA-histone tail literature refers to such contacts as "fuzzy contacts" because the histone tails adopt an ensemble of thermally accessible conformations, causing the residue sidechains to establish multiple energetically favorable nonbonded interactions (for example, coulombic, h-bonding, salt bridges, and cation-π). 66 Interestingly, we observed fuzzy contacts only in Segment I. Although Segments II and III lack secondary structure, their conformations are restricted by the proline hinges.…”