Outline the effect of acetylation of nucleosome tails on rates of gene expression.

Biochemistry. Author manuscript; available in PMC 2017 Jun 7.

Published in final edited form as:

PMCID: PMC5461660

NIHMSID: NIHMS861180

Abstract

Histone tails in nucleosomes play critical roles in regulation of many biological processes including chromatin compaction, transcription and DNA repair. Moreover, post-translational modifications, notably lysine acetylation, are crucial to these functions. While the tails have been intensively studied, how the structures and dynamics of tails are impacted by the presence of a nearby bulky DNA lesion is a frontier research area, and how these properties are impacted by tail lysine acetylation remains unexplored. To obtain molecular insight, we have utilized all atom 3 μs molecular dynamics simulations of nucleosome core particles (NCPs) to determine the impact of a nearby DNA lesion, 10S (+)-trans-anti-B[a]P-N2-dG--the major adduct derived from the procarcinogen benzo[a]pyrene--on H2B tail behavior in unacetylated and acetylated states. We similarly studied lesion-free NCPs to investigate the normal properties of the H2B tail in both states. In the lesion-free NCPs, the charge-neutralization upon lysine acetylation causes release of the tail from the DNA. When the lesion is present, it stably engulfs part of the nearby tail, impairing the interactions between DNA and tail. With the tail in an acetylated state, the lesion still interacts with part of it, although unstably. The lesion’s partial entrapment of the tail should hinder the tail from interacting with other nucleosomes, and other proteins such as acetylases, deacetylases and acetyl-lysine binding proteins, and thus disrupt critical tail-governed processes. Hence, the lesion would impede tail functions modulated by acetylation or deacetylation, causing aberrant chromatin structures and impaired biological transactions such as transcription and DNA repair.

Keywords: nucleosome core particle, benzo[a]pyrene-derived lesion, histone N-terminal tails, post-translational modification, lysine acetylation, all atom explicit molecular dynamics simulation, nucleotide excision repair, epigenetics

Graphical abstract

The nucleosome is the basic structural unit of chromatin;1 the nucleosome core particle (NCP) is composed of 145–147 base pairs of DNA wrapped left-handed with ~ 1.65 superhelical turns around the histone octamer, which contains an (H3-H4)2 tetramer and two (H2A-H2B) dimers, as well as positively charged histone tails that protrude from the histone octamer.2, 3 The histone octamer compacts DNA tightly into superhelical turns, and the histone tails have multiple functions, including mediating folding of nucleosomes into higher-order structures.4

The N-terminal histone tails are targets for post-translational modifications (PTMs) that modulate the functions of the histone tails, and thereby contribute to the regulation of various vital cellular processes.5–7 The PTMs on the tails directly mediate the packing of the nucleosomes into higher-order chromatin structures4 through their contacts to the DNA wrapped around the histone octamer,8 linker DNA9 and the acidic patch regions in neighboring nucleosomes.10 The PTMs on the tails attract histone modifiers that induce or remove modifications,11 and serve as platforms to recruit chromatin-binding proteins for chromatin remodeling.12–16

Lysine acetylation of the N-terminal tails is a key, charge-neutralizing, PTM that is involved in the regulation of many biological processes17, 18 including transcription19, 20 and DNA repair;7, 21–27 it is often deemed to be an epigenetic regulator in the broad sense--as a DNA-related regulatory mechanism that does not involve changes in the nucleotide sequence, regardless of whether it is strictly heritable.15 Hyperacetylation of histone tails in lightly packed euchromatin is associated with activation of transcription and repair, while hypoacetylation of the tails in tightly packed heterochromatin is associated with their repression. Errors in acetylation or deacetylation may contribute to aberrant chromatin structure and gene expression, and thereby perturb cellular processes. Such disturbance may lead to human diseases, including cancer,28 inflammatory diseases,29 Huntington’s disease,30 and aging-associated diseases.31

Each histone tail appears to have unique, essential functions that perform complex roles in regulating chromatin structure.5, 32 The individual tails play crucial and distinct roles in the stability of the nucleosome structure32–34 and in the compaction of chromatin fibers,35–37 and consequently, the governance of gene expression.

The H2B tail plays an important role in gene expression and DNA repair.23, 38–41 Studies with yeast have demonstrated that deletion of the H2B N-terminal domain residues 30 – 37 results in reduced nucleotide excision repair (NER) efficiency and contributes to increased ultraviolet (UV) sensitivity,38 and that mutants with deletion of this domain have enhanced nucleosome mobility and higher access to nucleosomal DNA.23 Deletion of the H2B tail in yeast cells upregulates a large number of yeast genes and causes significant loss of histone occupancy, which may cause partially assembled nucleosomes to be unstable; these observations revealed the essential role of this tail in repressing transcription23, 38 and in nucleosome assembly.39, 41 The key role of the H2B tail in regulating transcription is also shown in a study with human HeLa cells, which found that when the H2B tail is in its unacetylated state, Lys20 binds tumor suppressor P14ARF and thereby mediates transcription repression of cell cycle regulatory genes; this repression is lifted by tail acetylation.40

Intensive experimental35–37, 42–47 and computational48–56 studies have revealed a wealth of information about how lysine acetylation on the histone tails affects nucleosome and chromatin structures. Yet, how the structures and dynamics of tails are impacted by the presence of a nearby bulky DNA lesion is a frontier research area. The influence of such a bulky DNA lesion on unacetylated tail properties has been investigated, to the best of our knowledge, only in our prior study.57 Moreover, how the interactions between the lesion and the tail are impacted by histone tail lysine acetylation remains unexplored.

Benzo[a]pyrene (B[a]P) is the most well-studied member of a class of wide-spread environmental procarcinogens known as polycyclic aromatic hydrocarbons (PAHs), and is classified by the IARC58 (International Agency for Research on Cancer) as a human carcinogen. B[a]P is metabolically activated through the well-studied diol-epoxide pathway59 to the major reactive (+)-anti-benzo[a]pyrene diol epoxide (B[a]PDE), which is highly mutagenic60, 61 and tumorigenic.62, 63 B[a]PDE attacks DNA to form the predominant64, 65 and mutagenic66 10S (+)-trans-anti-B[a]P-N2-dG (B[a]P-dG) bulky adduct to DNA. It adopts a minor groove position in B-DNA in solution.67 Studies with nucleosomes utilizing B[a]PDE to form adducts have found that rotational setting of guanines in the nucleosomal DNA do not explain the observed level of adduction but that adduction was least near the dyad.68

Here we have carried out a comprehensive investigation of the effect of lysine acetylation on the properties of the H2B tail and its interactions with DNA, and we delineate how the B[a]P-dG lesion impacts the tail’s behavior in unacetylated and acetylated states. We carried out a series of ~ 3 μs molecular dynamics simulations with extensive analyses for four nucleosome core particle (NCP) models: (1) lesion-free NCP with unacetylated tail (lesion-free/unacetylated NCP); (2) lesion-free NCP with acetylated tail (lesion-free/acetylated NCP); (3) lesion-containing NCP with unacetylated tail (lesion-containing/unacetylated NCP); and (4) lesion-containing NCP with acetylated tail (lesion-containing/acetylated NCP). The lesion was placed at superhelical location (SHL) ~ 3 near the investigated full length H2B tail in a NCP. Our results reveal that as anticipated, the charge-neutralization upon lysine acetylation causes release of the tail from the lesion-free DNA, while the tail is collapsed on the DNA surface when unacetylated. When the B[a]P-dG lesion is present, it stably engulfs part of the nearby histone H2B tail, impairing the interactions between DNA and tail observed in the lesion-free case. Moreover, the lesion still interacts with part of the tail when it is acetylated, although unstably.

Our finding that the tail is released from nucleosomal DNA upon its acetylation supports the understanding that acetylation leads to chromatin opening for access to the DNA,45–47 and recruitment of other proteins that regulate processes such as transcription and DNA repair.12–16 On the other hand, the presence of the lesion, whether or not the tail is acetylated, causes the tail to be confined by its entrapment which would impair these normal tail functions.

MATERIALS AND METHODS

In order to elucidate the impact of a minor groove-situated B[a]P-dG lesion on the structures and dynamics of a histone tail in unacetylated and acetylated states, we performed MD simulations for the following four NCP models containing the H2B tail at SHL ~ 3: without further modifications (lesion-free/unacetylated NCP), with all lysine residues acetylated on the H2B tail (lesion-free/acetylated NCP), with a minor groove-situated B[a]P-dG lesion at SHL ~ 3 (lesion-containing/unacetylated NCP), and with lesion and tail acetylation (lesion-containing/acetylated NCP). The NCP model with lesion modification site and the histone tail lysine modification sites are shown in Figure 1.

NCP structure and positioning of histone H2B and its tail on the DNA in the investigated model. The model is based on crystal structures of PDB69 entry 2NZD70 and 1KX5,3 as described in Methods. (A) Best representative structure in the lesion-free/unacetylated NCP. Only half of the nucleosomal DNA, with SHL larger than zero (corresponding to gyre-1) is shown for clarity. The location of each base pair with respect to the histone core is designated by its superhelical location relative to the dyad position. The twofold pseudo-symmetry dyad axis is indicated. The dyad which is at the center of the 145 base pair DNA duplex has SHL = 0. The SHL increases by one unit for each successive turn of the double helix (~ 10 base pairs) in gyre-1 and the positions of the SHLs at 0 – 6 are indicated. The tail is at SHL ~ 3 and the Cα atom of the first residue from the N-terminus is shown as black dot. (B) Side view of the NCP structure showing the tail protruding between the two DNA gyres. Gyre-2 corresponds to the DNA double helix location with SHL < 0 (colored in grey). The lesion modification site is indicated with a pink star and the modified strand is Chain I from PDB69 entry 2NZD.70 The inset box shows the chemical structure (left panel) of the 10S (+)-trans-anti-B[a]P-N2-dG (B[a]P-dG) lesion and the best representative structure in the lesion-containing NCP (right panel). The B[a]P ring system is oriented in the 5′-direction of Chain I, and Watson-Crick pairing at the lesion site is maintained in the simulation as in the NMR solution structure.67 The B[a]P-dG lesion is colored by atom with carbons in green. Lysine acetylation sites on the H2B N-terminal tail are designated as red spheres. (C) The sequence of the H2B N-terminal tail, including the residue numbering (corresponding to the numbers in Chain D of the crystal structure of PDB69 entry 1KX53, and sites for lysine acetylation (Ac). Positively and negatively charged residues are red and blue, respectively. Note that the first three residues (PEP) of the H2B tail in Xenopus laevis are missing in this PDB69 entry 1KX53. Therefore, the number of the first residue (Ala) in crystal structure 1KX53, that we employed, corresponds to the 4th residue in Xenopus laevis.

Initial nucleosome core particle models for MD simulations

We built an initial model for our simulations which contains only one full length tail, the histone H2B tail (Figure 1A). This initial model is a hybrid NCP model. We began with the NCP with PDB69 entry 2NZD70 where all the histone tails are truncated -- including the H2B tail of interest at SHL ~ 3, whose coordinates for residues 1 to 27 from the N terminus were not deposited in the PDB. We modeled in these residues based on the NCP with PDB 69 entry 1KX5 3, in which full length tails were generally resolved. However, many atoms of amino acids in in the NCP tails have zero occupancies and/or very high thermal factors. Accordingly, we did not model the first three residues of the H2B tail since the coordinates are missing. The H2B tail at SHL ~ 3 is between the two DNA gyres (Figure 1B). Note that 1KX53 contains the same histones as 2NZD.70 All other models for our simulations were based on this hybrid model (lesion-free/unacetylated NCP). We acetylated all the lysine residues in the H2B tail (see Figure 1C for tail sequence) for our simulation to investigate the impact of lysine acetylation (lesion-free/acetylated NCP); this optimizes the possibility of defining the structural and dynamic impacts of acetylation. Furthermore, we were interested in understanding whether the tail structures and dynamics were impacted by the lesion. Accordingly, we modeled in the minor groove-situated B[a]P-dG lesion, based on the NMR solution structure 67 (see inset box in Figure 1) at SHL ~ 3, where the H2B tail is nearby and the lesion in the minor groove faces the tail (lesion-containing/unacetylated NCP) (Figure S1 of the Supporting Information (SI)). We selected the only guanine in this vicinity that situates the B[a]P-dG lesion in the minor groove, facing outward toward the H2B tail. The local DNA 11-mer sequence for each gyre and the precise lesion modification site is given in Figure S1 in SI. Similarly, we acetylated lysine residues in the tail for the lesion-containing case (lesion-containing/acetylated NCP).

Simulation methods

For the simulations of these four NCP models, we conducted ~ 3 – 3.5 μs MD simulations using the AMBER1471 package with force field ff14SB72 for histones and incorporated modifications73–75 for nucleosomal DNA. We used the Joung-Cheatham76 model for the K+ ions. The TIP3P77 model was used for water, and K+ ions were added to neutralize the system. The number of waters, box sizes, and the length of the simulation for the investigated NCP models are summarized in Table S1 in SI.

Post-processing of all simulations was carried out using the CPPTRAJ78 module of AMBER14.71 All structural analyses were obtained from these MD simulations with the first 1.5 μs discarded. This was based on the 2D RMSDs (Figure S2 in SI) of the tail conformation, showing that stable tail structures were achieved after ~ 1.5 μs in the lesion-free/unacetylated NCP. In other NCP cases, the structures fluctuated throughout the simulations compared to this lesion-free/unacetylated NCP.

PyMOL (The PyMOL Molecular Graphic System, version 1.3x, Schrödinger, LLC) and VMD79 were employed for molecular modeling, images and movies.

Full details concerning preparation of NCP models, force field, MD simulation protocol, and structural analyses are given in the Methods section in SI.

RESULTS

In the lesion-free/unacetylated NCP, the tail is collapsed onto the DNA surface, unstructured and extended

We have investigated the structure and dynamics of the H2B tail in the lesion-free/unacetylated NCP, with a ~ 3 μs MD simulation. In the initial model (see Materials and Methods section), the H2B tail residues are mostly between the two DNA gyres at SHL ~ 3. The snapshots of the tail along the MD simulation (Figure S3 in SI) show that the tail remains between the two gyres initially up to ~ 1 μs. Afterward, the tail becomes transiently solvent exposed (Figure S3C), and subsequently, at ~ 1.5 μs, the tail collapses onto one of the DNA gyres (gyre-1, Figure 2A, Movie S1), interacts stably with the DNA surface (Figure 2B; Figure S4A in SI), and forms an extended conformation (Figure 2C). Because of the stable collapse of the tail onto the DNA, the tail dynamics is inhibited, as revealed in ensemble average RMSF values in Figure 2A, and the tail samples a limited conformation space (Figure S2A in SI).

Impact of lysine acetylation on the histone H2B tail in lesion-free NCPs. (A) Acetylation causes the tail to be released from the DNA, which makes it more solvent exposed and dynamic. This is shown in the greater ensemble average values of the tail backbone heavy atoms root-mean-squared fluctuations (RMSF), and in the tail ensemble structures. Top and side views are given. (B) Acetylation reduces the DNA-tail contact surface area (CSA), as shown by the distributions of the DNA-tail CSA. Details of specific interactions between DNA base pairs and histone tail amino acids are given in Figure S4. Structures shown, designated by an asterisk(*) on the CSA, are representative of the highest population clusters. Acetylation causes the tail to be more compact. This is shown by (C) the distributions of the tail radii of gyration (Rg) and by (D) their increased folded, helix and β strand, propensity. In (A) the best representative NCP structure from the MD ensemble is shown, except for the H2B tail for which snapshots at 100 ns intervals are presented; the H2B N-terminal tail is rendered as cartoon in red, the histone core as surface in cyan, and the DNA as surface with backbone in blue and bases in gray. In (B) and (D), the Cα atom of the first residue from the N-terminus is shown as black dot. See Movies S1 and S2.

In this collapsed and extended state of the tail, there are favorable electrostatic interactions between the negatively charged DNA phosphate groups and the large proportion of positively charged lysine and arginine residues in the tail (14 lysine and arginine residues out of 34 tail residues, shown in Figure 1C); electrostatic repulsions between positively charged lysine residues are minimized due to the increased pair-wise distances between these charged residues, and DNA-tail electrostatic attractions are optimized with extension of the tail (Figure 2B; Table S2 and Figure S5 in SI). The tail extension is quantitatively revealed in the radii of gyration (Figure 2C), which show a narrowly clustered population that is closer to an extended, denatured random coil than to a compact, globular state. Consistent with the extended state of the tail, helical content (Figure 2D), including α helix and 310 helix, is very limited. It occurs only between residues 14 and 17 (corresponding to residues Ala14, Val15, Thr16, and Lys17) and is only ~ 33% of the population, and is absent in other regions of the tail.80 Furthermore, the helices are unstable, fluctuating between helical and turn conformations every few nanoseconds (Figure S6A in SI). Favorable electrostatic interactions between lysine residues and the DNA backbone impede formation of stable helical forms in the tail,81 and repulsions between positively charged lysine residues that are near each other also destabilize compact helical structures.42, 50 Prior MD simulations have also observed collapse of the histone tails on the nucleosomal DNA,55, 81–85 as well as transient helical states in the tails.81, 84

In the lesion-free/acetylated NCP, the tail is released from the DNA surface and assumes a compact structure

We wished to explore the effect that lysine acetylation has on the tail structure and dynamics. The overarching impact of lysine acetylation on the histone tail is due to attendant charge neutralization and increased hydrophobicity, and important effects of the acetylation stem from these phenomena. Specifically, the N-terminal tail residues 1 to 25 are released from the DNA surface, especially on the major groove side, and adopt a compact conformation that is modestly more dynamic than the unacetylated tail, as shown in Figure 2A. The release of the tail from the DNA is explained by the significant reduction in favorable DNA-tail interactions upon acetylation (Figure 2B; Table S3, Figure S4B, and Movie S2 in SI). Nonetheless, the tail remains in the vicinity of the DNA. Furthermore, these weakened DNA-tail interactions cause the DNA to be more dynamic (Figure S7 in SI) including greater fluctuations in the minor groove widths (Figure S8 in SI).

The compaction of the tail is due to decreased intra-tail repulsion between the positively charged lysine residues and increased intra-tail hydrophobic interactions, such as van der Waals interactions between acetyl methyl groups, that shorten the distance between them (Figure S5 in SI). The radii of gyration quantitatively demonstrate this compaction, with the peak greatly shifted toward the compact globular domain (Figure 2C). Furthermore, the tail adopts a stable β hairpin conformation, involving residues 12 to 21, with flickering helical structure within these residues (Figure 2D; Figure S6B in SI), which is consistent with the tail compaction.

In the lesion-containing/unacetylated NCP, part of the tail is stably engulfed by the B[a]P rings while part is fully solvent exposed

Our prior 800 ns MD study57 of the NCP containing the DNA minor groove B[a]P-dG lesion (see inset box in Figure 1) positioned at SHL ~ 3 near the H2B tail, showed that part of the tail is tightly engulfed by the B[a]P ring system’s enlarged minor groove. Here we extended the simulation to ~ 3.5 μs. We wished to further assess the stability of the tail entrapment, to consider the characteristics of the unengulfed part of the tail, and to elucidate the impact of lysine acetylation on the entire tail, including its entrapped region and beyond.

Our extended simulation shows that the features of the engulfed tail from the first 800 ns simulation persist to 3.5 μs; tail residues 14 – 24 form a stable loop and most residues between 16 and 26 are collapsed stably on the B[a]P ring system in the enlarged minor groove (Figure 3A; Figure S8A, Movie S3 in SI). Therefore, most DNA-tail contacts are in the lesion-containing minor groove (Figure 3B; Figure S4C in SI). The tail entrapment is stabilized by a network of interactions: favorable van der Waals (Figure S9A), hydrogen bonds (Figure S9B, Table S4 in SI), and methyl-π (Me-π) interactions (Figure S9C in SI) between the B[a]P aromatic rings and the tail, as well as interactions between the DNA and the tail (Table S5 in SI). Figure 3A and Figure S9A show specific van der Waals interactions between B[a]P rings and amino acids Thr16, Lys17, Thr18, Gln19, and Arg26. In addition, intra-tail hydrogen bond interactions contribute to the stability of the tail loop (Table S6, Figure S9D–E in SI), causing the tail in this region to be more compact (Figure 3C), with a stable β hairpin loop (Figure 3D).

Impact of minor groove situated B[a]P-dG lesion on the histone H2B tail in lesion-containing NCPs. (A) The state of acetylation of the H2B tail determines the stability of its engulfment by the B[a]P ring system. The unacetylated tail residues 14 to 26 form a stable loop and most of these residues are tightly entrapped in the lesion-imposed enlarged-minor groove (see “Engulfed tail” in blue box); the first 13 residues from the N-terminus become solvent exposed (see “Unengulfed tail” in blue box). The acetylated tail oscillates between two conformations, one (state-1) in which it is in the lesion-containing minor groove, and a second (state-2) where it is housed between the two DNA gyres (right panel, green box). The van der Waals interactions between the B[a]P ring system and the tail residues (ACK13, ACK20, ACK21, ACK25) are always unstable (Figure S10, SI), causing the acetylated tail to be dynamic, as shown in the greater ensemble average RMSF values, and in the tail ensemble structures. (B) DNA-tail contact surface areas (CSA) are similar in both unacetylated (mean values: 813±54 Å2) and acetylated NCPs (mean values: 858±110 Å2), but the CSA is broader and bimodal in the acetylated NCP, while there is a single sharp peak for the unacetylated case and the structure shown, designated by an asterisk (*) on the CSA, is representative of the highest population cluster. Details of specific interactions between DNA base pairs and histone tail amino acids are given in Figure S4. (C) The distributions of the tail radii of gyration (Rg) also reveal a single peak in the unacetylated tail and bimodal states in the acetylated case, with state-1 extended and state-2 compact, revealing great conformational variability. (D) The lesion inhibits helical conformations by interacting with the tail, as shown by decreased helical propensity in the engulfed region. In (A) the best representative NCP structure from the MD ensemble is shown, except for the H2B tail for which snapshots at 100 ns intervals are presented; the H2B N-terminal tail is rendered as cartoon in red, the 6histone core as surface in cyan, and the DNA as surface with backbone in blue and bases in gray. In (B) and (D) the Ca atom of the first residue from the N-terminus is shown as black dot. See Movies S3 and S4.

Beyond the engulfed region, tail residues 1 – 12 are released from the DNA, solvent exposed and mobile (Figure 3A; Movie S3 in SI). Therefore, the DNA-tail contact surface area is significantly reduced by the presence of the lesion, with peak value of ~ 800 (Å2) (Figure 3B), compared to the peak value of ~ 1300 (Å2) for the lesion-free/unacetylated NCP (Figure 2B). The enhanced mobility of these released residues is revealed in their ensemble average RMSF values (Figure 3A) and also the wider distribution of their radii of gyration (Figure 3C). The released tail residues are mostly unstructured, adopting ~ 30 %, flickering helical conformations between residues 8 and 12 (Figure 3D, Figure S6C in SI). Because of the released N-terminal tail residues, the DNA near the lesion, including the minor groove widths (Figure S8 in SI), is more dynamic compared to the lesion-free case (Figure S7 in SI).

In the lesion-containing/acetylated NCP, the tail undergoes large conformational transitions between two states, while maintaining contact with the B[a]P rings

The B[a]P ring system remains an attractor to the tail residues in the lesion-containing/acetylated NCP. When the lysine residues are acetylated, the tail becomes less charged and more hydrophobic; hence, the DNA-tail interactions are weakened (Table S7, Figure S4D in SI). However, van der Waals interactions between the B[a]P rings and the tail remain, specifically between the acetyl lysine side chain and the B[a]P rings, but these interactions fluctuate greatly due to the reduced electrostatic interactions (Figures S10 and S11 in SI). Hence, the tail oscillates mainly between two conformations (Figure 3A, Movie S4 in SI): in one conformation (state-1) the tail is in the lesion-containing minor groove and has relatively more van der Waals interactions with the lesion rings; in the second conformation (state-2) the tail is housed between the two gyres and has relatively less van der Waals interactions with the lesion rings. Regardless of the state, the tail always contacts the B[a]P aromatic rings through mainly van der Waals and hydrogen bond (Table S8 in SI) interactions, although unstably. Analyses of the two separately clustered states of the tail are given in Figure S12 in SI.

Ensemble average values for various tail characteristics are in line with the tail conformational interchange; the tail residues are very dynamic as shown in their RMSF values (Figure 3A); the distribution of the DNA-tail CSA is broad (Figure 3B); and there are multiple populations (state-1, state-2, and intermediate states) in the tail radii of gyration (Figure 3C): the population with the tail between the two gyres has a peak at ~ 8 Å that is near the globular domain and is compact due to internal van der Waals interactions within the tail that involve acetyl groups; the second population with tail in the minor groove has larger radii of gyration, reflecting its greater extension. Notably, the folded propensities (helical and β structures) of the acetylated tail are greatly reduced by the presence of the lesion regardless of the states (Figure 3D). This is because the lesion-tail interactions outcompete the intra-tail hydrogen bonds needed to form the helical or β conformations. Therefore, the interactions between the histone tail and the B[a]P ring system tend to destabilize the tail folded structures.

Lysine acetylation not only causes the tail to be more dynamic, but also allows the DNA to be more dynamic (Figure S7 in SI), including increased minor groove dynamics (Figure S8B in SI). Among our investigated systems, the DNA is the most dynamic when the lesion is present and the tail is acetylated.

DISCUSSION

In the present study, we wished to gain insight on how the presence of a lesion derived from the carcinogen benzo[a]pyrene in the nucleosome would likely disrupt the multiple biological functions of histone tails, in both unacetylated and acetylated states. For this purpose, we have carried out four simulations of NCP models, namely lesion-free/unacetylated, lesion-free/acetylated, lesion-containing/unacetylated, and lesion-containing/acetylated NCPs. We have utilized ~ 3 μs molecular dynamics simulations of individual NCP models to obtain detailed understanding of the impact that a benzo[a]pyrene-derived DNA lesion, B[a]P-dG, and lysine acetylation have on the tail structures, dynamics and interactions with nucleosomal DNA. Our MD simulations focus only on a single H2B tail; this has the advantage that it permits pinpointing the structures and interactions between a single tail, the local DNA and the carcinogen. However, it neglects the effects of the other tails on these phenomena, which is a fertile area for exploration, particularly involving DNA lesions. Experimental studies have shown for the histone tails that their functions are not necessarily independent.32 In addition, we acetylated all lysines in the H2B tail; this optimizes the possibility of defining the structural and dynamic impacts of acetylation, and has the advantage of avoiding the need to choose specific lysines for acetylation, since these are variable and species-dependent.18, 55, 86 For each case, we have analyzed in detail structural and dynamic properties of the H2B tail; specifically we have evaluated DNA-tail interactions, the DNA and tail dynamics, as well as tail structures, and have determined how the lesion inhibits the normal tail behavior in unacetylated and acetylated states. A summary of our key findings is given in Figure 4.

Impact of lysine acetylation and the presence of the lesion on the tail conformation in the NCP, showing that the lesion disrupts the normal tail behavior. Color code: DNA, gray; H2B tail, red; lysine or acetyl lysine residues, blue sticks; acetyl group, colored by atom with carbons in yellow; B[a]P ring system, colored by atom with carbons in green; DNA-tail contact surface area: light blue surface.

Acetylation reduces DNA-tail contact, making DNA and the tail available for other interactions

Our results showed, in the case of the lesion-free NCPs, that the unacetylated tail is collapsed onto the DNA surface while the acetylated tail, released from the DNA surface but remaining in its vicinity, assumes a more compact structure. These phenomena result from the lysine charge neutralization upon acetylation; electrostatic DNA-histone attractions and histone-histone repulsions are decreased, and hydrophobic interactions among the tail acetyl groups are increased (Figure S5 in SI). Therefore, acetylation reduces the contact between the DNA and the tail (Figure 2B), thereby allowing the unbound DNA to be more dynamic (Figure S7 in SI) and accessible. In addition, the released tail contains persistent β hairpin structures that contain flickering helices within the loop (Figure 2D), which render the tail to be more compact (Figure 2C). The well-known function of lysine acetylation in facilitating DNA accessibility34, 45–47 would be promoted by the release of the tail from the DNA, the attendant enhanced DNA mobility and the compaction of the released tail. Other computational studies have supported that acetylation causes decreased DNA-tail contact50, 53, 55 and increased compaction of the tail due to formation of secondary structure.49, 50, 52, 53, 55, 56 Moreover, the helical and β content and the balance between them may depend on the specific tail. In addition, various experiments have revealed that acetylation increases DNA dynamics, nucleosome accessibility, and tail helical structure. A crystal structure of a NCP with a tetra-acetylated H4 tail and an unacetylated tail showed that acetylation increased the B-factor (reflecting mobility) of nearby DNA.43 It was recently reported that when the histone H4 tail is modified by “acetylation mimics”, in which positively charged lysines are replaced by uncharged glutamines, accessibility in the immediate vicinity of the nucleosome is increased. When the H3 tail was additionally modified similarly, there was a synergistic effect to further increase the nucleosome accessibility.45 Circular dichroism (CD) studies42 have shown increased a-helical content with acetylation, consistent with a more compact conformation of the investigated H4 tail.

Our simulations may help provide molecular interpretations to the interesting experimental work of Wang and Hayes 87, who studied the effect of mimics of up to 9 lysine acetylations on the H2B tail interactions with DNA. Structurally, in our simulations, the tail is extended (elongated) and collapsed onto the DNA surface when unacetylated; however, when acetylated it is more condensed (Figure 2C) with enhanced folded states (Figure 2D), and released from the DNA, while remaining in its vicinity (Figure 2B). This is consistent with the suggestion87 that acetylation “causes localized alterations in tail binding. These alterations may be related to specific structural changes in tail structure detected by spectroscopic techniques.42, 88”

It has been suggested that tail compaction decreases the tail availability for crucial internucleosomal interactions in chromatin compaction53 and induces unwrapping of linker DNA to provide greater access to the DNA.50 The more condensed tail conformation could act as a docking site for acetyl-lysine binding proteins; this is in line with a structural study that highlights the importance of multiply acetylated tails, which has shown that closely-packed, clustered acetylation sites provide recognition motifs for hydrophobic cavities in acetyl-lysine binding proteins.14

Engulfment of part of the tail by the B[a]P-dG lesion would disrupt critical tail functions

In the presence of the B[a]P-dG lesion, a part of the unacetylated tail is stably engulfed by the B[a]P ring system. When the tail is acetylated, it still partly contacts the B[a]P rings, mainly through van der Waals interactions via acetyl groups, but the interactions are unstable (Figures S10 and S11 in SI); the tail oscillates between being housed in the lesion-containing minor groove or between the two gyres (Figure 3A), due to competing interactions between the tail and B[a]P rings or intra-tail interactions. Consequently, the tail-DNA contact pattern, the DNA and the tail are more dynamic in the acetylated case (Figure 3).

Biologically, the B[a]P-dG lesion’s partial entrapment of the tail should hinder the tail from interacting with other nucleosomes, and other proteins such as acetylases, deacetylases and acetyl-lysine binding proteins, and thereby disrupt critical tail functions. Thus, the entrapped tail would inhibit acetylation/deacetylation or other modifications for achieving access to the DNA. Furthermore, engulfment of part of the tail limits the ability of the tail to extend or compact when needed. This limitation to extension for the unacetylated tail would inhibit the ability of the tail to reach out to neighboring nucleosomes, and thereby diminish crucial histone-histone or histone-DNA interactions, and possibly lead to chromatin decondensation; the restraint on compaction for the acetylated tail could prevent formation of structural motifs needed for recognition by various chromatin remodeling proteins.14

Recently, it has been found that acrolein, a major component of cigarette smoke and cooking fumes, reacts with histone H4 tail lysine residues to form an acrolein adduct, which inhibits lysine acetylation and therefore disrupts interactions of the tail with binding factors needed for nucleosome41 and chromatin assembly.89, 90 Greenberg and coworkers have shown that DNA abasic lesions react with tail lysine residues to form cross-links whose rates of formation depend on the translational setting of the lesion in the nucleosome; furthermore, they have suggested that such cross-links would impede histone tail post-translational modifications.91, 92 Additionally, it has recently been shown for histone H2B in vivo, that the suspected human carcinogen furan can produce a cross-link adduct with a non-tail lysine residue that is crucial for nucleosome stability and a target for PTMs; impaired PTM and subsequent alterations in gene expression could result.93 Finally, our findings that the DNA is more dynamic with the B[a]P-dG lesion present, and even more so when the tail is acetylated, suggest that this mobility may be a signal that facilitates access to the lesion by the nucleotide excision repair machinery, which is responsible for their removal, according to the “access, repair, restore” paradigm pioneered by Smerdon.94, 95

In conclusion, our molecular dynamics simulations suggest that interactions of histone tails with bulky DNA lesions would impede the normal functions of the tails that are currently of great interest but yet poorly understood. The roles of the different tails and how these interact with different lesions, which may be positioned at various rotational and translational settings, are areas of great interest for future work.

Supplementary Material

Movie S1

Movie S2

Movie S3

Movie S4

Supporting Information

Acknowledgments

Funding Source Statement

This work was supported by NIH, NIEHS Grant R01-ES025987 and NCI Grants R01-CA28038 and R01-CA75449 (to S.B.), CA-168469 (to N.E.G.), and R01-GM079223 (to Y.Z.).

We gratefully acknowledge resources provided by the Extreme Science and Engineering Discovery Environment (XSEDE), which is supported by National Science Foundation (NSF), Grant MCB060037 to S.B., and the NYU IT High Performance Computing Resources and Services.

ABBREVIATIONS

Footnotes

Note

The authors declare no competing financial interest.

Supporting Information

The Supporting Information is available free of charge on the ACS Publications website. This material includes Supplementary methods, tables, figures (PDF), and Movies S1 – S4 (AVI).

Table S1, details of the MD simulations for the investigated NCP models; Table S2, hydrogen bond analyses between DNA and tail in the lesion-free/unacetylated NCP; Table S3, hydrogen bond analyses between DNA and tail in the lesion-free/acetylated NCP; Table S4, hydrogen bond analyses between tail lysine 17 and B[a]P ring system in the lesion-containing/unacetylated NCP; Table S5, hydrogen bond analyses between DNA and tail in the lesion-containing/unacetylated NCP; Table S6, hydrogen bond analyses between the residues within the tail in the lesion-containing/unacetylated NCP; Table S7, hydrogen bond analyses between DNA and tail in the lesion-containing/acetylated NCP; Table S8, hydrogen bond analyses between tail acetylated lysine residues and B[a]P ring system in the lesion-containing/acetylated NCP; Figure S1, structure and sequence of DNA gyres around H2B tail; Figure S2, 2D RMSDs of four investigated NCPs; Figure S3, tail trajectory along the MD simulation in the lesion-free/unacetylated NCP; Figure S4, contact maps between DNA and tail residues in the NCPs; Figure S5, DNA-lysine/acetylated lysine residue contact surface area and pair-wise distances of lysine/acetylated lysine residues in the tail in lesion-free NCPs; Figure S6, secondary structure of the tail in the NCPs; Figure S7, RMSFs of the DNA in the NCPs; Figure S8, minor groove width in the NCPs; Figure S9, entrapment of the tail by the B[a]P ring system through a network of interactions in the lesion-containing/unacetylated NCP; Figure S10, van der Waals interaction energies between the B[a]P ring system and tail residues in the lesion-containing/acetylated NCP; Figure S11, comparison of the tail-lesion aromatic ring van der Waals interactions; Figure S12, structural and dynamics analyses of two conformations of the tail in the lesion-containing/acetylated NCP; Movie S1, best representative structure of lesion-free/unacetylated NCP; Movie S2, best representative structure of lesion-free/acetylated NCP; Movie S3, entrapment of the tail by the B[a]P-dG lesion in the lesion-containing/unacetylated NCP; Movie S4, entrapment of the tail by the B[a]P-dG lesion in the lesion-containing/acetylated NCP.

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