Nucleosome Sliding: Mechanisms and Biological Significance
By Dr. Zubair Khalid, DVM, MS, PhD ·
Introduction to Nucleosome Sliding
What is Nucleosome Sliding?
Nucleosome sliding is the process by which a nucleosome—the fundamental repeating unit of chromatin—repositions itself along the DNA double helix without being disassembled. During sliding, the histone octamer remains intact, and the DNA that is wrapped around it changes position relative to the underlying DNA sequence. The result is that a nucleosome that was previously centered at one genomic location may now be centered 10, 20, or even 50 base pairs away. This movement is not random in the sense of being biologically meaningless; rather, it is a tightly regulated process that determines which DNA sequences are accessible to the cellular machinery.
To understand sliding, you must first appreciate that the nucleosome is not a rigid, immovable object. The canonical view of a nucleosome—a histone octamer with 147 base pairs of DNA wrapped around it in 1.65 superhelical turns—is accurate for the static structure, but it fails to capture the dynamic behavior of the particle in living cells. Nucleosomes undergo continuous conformational fluctuations, and sliding is one manifestation of this intrinsic dynamism. The term "sliding" specifically refers to the lateral movement of the histone octamer relative to the DNA, as opposed to other remodeling outcomes such as histone eviction, histone exchange, or changes in nucleosome spacing.
Why Nucleosome Sliding Matters
Nucleosome sliding is a central mechanism in chromatin biology because it directly controls DNA accessibility. The wrapping of DNA around the histone octamer occludes sequence-specific binding sites for transcription factors, replication proteins, and repair enzymes. By repositioning nucleosomes, cells can expose or occlude regulatory elements such as promoters, enhancers, and origins of replication. This makes sliding a primary determinant of gene expression patterns, cell fate decisions, and genome stability.
Consider a promoter region: if a nucleosome is positioned directly over the TATA box or the transcription start site, RNA polymerase II cannot initiate transcription. Sliding that nucleosome away by even 30–40 base pairs can expose the core promoter elements and permit transcription. Conversely, sliding a nucleosome over an enhancer element can silence a gene. This bidirectional control is exploited extensively during development, differentiation, and stress responses. The importance of nucleosome sliding is underscored by the fact that mutations in chromatin remodeling complexes—the enzymes that catalyze sliding—are associated with numerous cancers and developmental disorders.
The Nucleosome Structure and Its Dynamic Nature
Core Histone Octamer and DNA Wrap
The nucleosome core particle consists of an octamer of four core histone proteins—H2A, H2B, H3, and H4—each present in two copies. The octamer forms a disk-like structure around which 147 base pairs of DNA are wrapped in a left-handed superhelix. The DNA makes 1.65 turns around the histone octamer, with the entry and exit points of the DNA located on the same side of the particle. The structure is stabilized by electrostatic interactions between the negatively charged phosphate backbone of DNA and positively charged lysine and arginine residues on the histone proteins.
The histone fold domains—a conserved structural motif shared by all four core histones—form the globular core of the octamer. The N-terminal tails of the histones protrude from the nucleosome and are subject to extensive post-translational modifications such as acetylation, methylation, and phosphorylation. These tails do not contribute significantly to the stability of the DNA wrap but serve as platforms for recruiting regulatory proteins. For a more detailed review of the core particle, see the Nucleosome Structure entry.
Histone-DNA Interactions
The interaction between histones and DNA is not uniform along the wrapped segment. There are 14 distinct contact points where the DNA minor groove faces inward toward the histone octamer. These contacts are mediated primarily by hydrogen bonds between the protein backbone and the DNA phosphate groups, as well as by salt bridges involving arginine residues that insert into the minor groove. The strength of these interactions varies along the DNA: the central 20–30 base pairs (the dyad region) make the strongest contacts, while the entry and exit regions are more weakly bound.
This non-uniform interaction profile has profound implications for sliding. The entry and exit sites of the nucleosome are relatively labile, meaning that DNA can transiently unwrap and rewrap at these positions. This "breathing" of the nucleosome is a prerequisite for many sliding mechanisms. The strong central contacts, by contrast, act as an anchor that must be disrupted for the nucleosome to move. Understanding this energetic landscape is essential for grasping why sliding is not a simple diffusion process but rather a series of coordinated disruptions and re-formations of histone-DNA contacts.
Mechanisms of Nucleosome Sliding
Brownian Motion and Spontaneous Sliding
Nucleosomes can slide spontaneously, without the input of external energy, through a process driven by thermal fluctuations. This is known as Brownian sliding or thermal diffusion. The histone octamer is held in place by a series of weak, non-covalent interactions with DNA. At physiological temperatures, these interactions are constantly breaking and reforming. Occasionally, a coordinated series of breakages allows the octamer to shift by a small number of base pairs.
The rate of spontaneous sliding is highly dependent on the DNA sequence. Certain sequences, particularly those rich in AT base pairs, are more flexible and allow for faster sliding. In contrast, GC-rich sequences form more rigid DNA that resists bending around the octamer. In vitro measurements have shown that spontaneous sliding can reposition nucleosomes by tens of base pairs over timescales of hours to days, depending on the sequence and ionic conditions. This is far too slow to account for the rapid chromatin rearrangements observed in cells, which occur within seconds to minutes. Nevertheless, spontaneous sliding is biologically relevant: it provides a baseline level of nucleosome mobility and contributes to the establishment of nucleosome positioning patterns on certain genomic elements.
ATP-Dependent Remodeling
The vast majority of regulated nucleosome sliding in cells is catalyzed by ATP-dependent chromatin remodeling complexes. These are multi-subunit enzymes that use the energy from ATP hydrolysis to actively reposition nucleosomes. All remodeling complexes contain a conserved ATPase subunit belonging to the SNF2 family of helicase-related proteins. This ATPase domain translocates along DNA, generating the mechanical force needed to move the histone octamer.
The ATPase motor works by binding to the nucleosome at a specific location—typically near the entry site of the DNA—and then pumping DNA toward the dyad. This creates a transient bulge or loop of DNA on the nucleosome surface. The loop propagates around the octamer, and as it resolves, the histone octamer ends up at a new position relative to the DNA. The direction of sliding is determined by the orientation of the ATPase motor and the geometry of its interaction with the nucleosome.
ATP-dependent remodeling is processive: a single remodeling complex can move a nucleosome by dozens or even hundreds of base pairs before dissociating. The rate of sliding is typically 1–5 base pairs per second under saturating ATP conditions in vitro. This is several orders of magnitude faster than spontaneous sliding and explains how cells can rapidly reprogram their chromatin landscape in response to signals.
Twist-Defect Model
The twist-defect model is one of the two principal mechanisms proposed to explain how nucleosomes move. In this model, a small perturbation in the DNA twist—a "defect"—is introduced at one location on the nucleosome. This defect is a local change in the number of base pairs per helical turn, effectively creating a region where the DNA is slightly over- or under-wound. The defect then propagates around the histone octamer like a wave, moving from the entry site toward the exit site.
As the twist defect travels, it shifts the register of histone-DNA contacts. Each contact point must be broken and re-formed as the defect passes, but this happens sequentially rather than all at once. The net effect is that the histone octamer moves by approximately one base pair for each twist defect that traverses the nucleosome. The twist-defect model is particularly appealing because it explains how nucleosomes can move in small, discrete steps and why the movement is often observed to occur in increments of 1–2 base pairs.
The energy barrier for twist-defect propagation is relatively low, which is consistent with the observation that spontaneous sliding can occur at measurable rates. However, ATP-dependent remodelers accelerate this process by actively generating and propagating twist defects. The ATPase motor of the remodeler introduces a torsional strain into the DNA, which then relaxes by forming a twist defect that propagates around the octamer.
Loop-Recapture Model
The loop-recapture model, also known as the bulge propagation model, offers an alternative mechanism. In this model, the DNA at the entry site of the nucleosome is transiently unwrapped from the histone surface. The ATPase motor of a remodeling complex then pumps additional DNA into this unwrapped region, creating a loop or bulge of DNA that is not in contact with the histones. This loop grows as more DNA is pumped in, and it travels around the histone octamer like a wave traveling around a cylinder.
When the loop reaches the exit site, it is "recaptured"—the DNA in the loop re-associates with the histone surface. The net result is that a segment of DNA that was originally on one side of the nucleosome has been transferred to the other side, effectively moving the histone octamer relative to the DNA. The loop-recapture model can account for larger movements than the twist-defect model, as a single loop can contain 10–50 base pairs of DNA.
The loop-recapture model is strongly supported by single-molecule experiments that have directly observed the formation and propagation of DNA bulges on nucleosomes. These experiments have shown that the bulge forms at the entry site, grows in size, and then collapses at the exit site, consistent with the predictions of the model. Both the twist-defect and loop-recapture mechanisms likely operate in cells, with the relative contribution of each depending on the specific remodeling complex and the local chromatin context.
Key Players: Chromatin Remodeling Complexes
SWI/SNF Family
The SWI/SNF (Switch/Sucrose Non-Fermentable) family is named after the yeast genes that were first identified as regulators of mating-type switching and sucrose fermentation. The ATPase subunit in this family is either BRM (Brahma) or BRG1 (Brahma-Related Gene 1) in humans. SWI/SNF complexes are large, multi-subunit assemblies that are best known for their ability to slide and evict nucleosomes. They are particularly important for activating gene expression by opening up chromatin at promoters and enhancers.
SWI/SNF complexes contain a unique subunit called an actin-related protein (Arp) that is thought to regulate the processivity of the ATPase motor. Unlike some other remodelers, SWI/SNF complexes do not require a specific histone modification to bind nucleosomes; instead, they are recruited by sequence-specific transcription factors. Mutations in SWI/SNF subunits are found in approximately 20% of human cancers, highlighting the critical role of this family in tumor suppression.
ISWI Family
The ISWI (Imitation SWI) family is named after the Drosophila protein that was identified as a homolog of the yeast SWI2/SNF2 ATPase. The human genome encodes two ISWI ATPases: SNF2H and SNF2L. ISWI complexes are primarily involved in the assembly of regularly spaced nucleosome arrays—the "beads on a string" structure of chromatin. They slide nucleosomes to generate uniform spacing, which is important for chromatin compaction and for the proper functioning of heterochromatin.
ISWI complexes have a distinctive feature: they contain a SANT domain that binds to unmodified histone H3 tails. This interaction is essential for their spacing activity. ISWI complexes are also regulated by acetylation of histone H4 at lysine 16 (H4K16ac), which inhibits their nucleosome sliding activity. This provides a mechanism for coordinating nucleosome spacing with transcriptional activation, as H4K16ac is associated with active chromatin.
CHD Family
The CHD (Chromodomain-Helicase-DNA binding) family is characterized by the presence of chromodomains, which are protein modules that bind to methylated lysine residues on histone tails. The human genome encodes nine CHD proteins, which are divided into three subfamilies. CHD1 and CHD2 are involved in transcription elongation and are found at actively transcribed genes. CHD3 and CHD4 are components of the NuRD (Nucleosome Remodeling and Deacetylase) complex, which couples nucleosome sliding with histone deacetylation to repress transcription.
CHD proteins are unique among remodelers in that they can slide nucleosomes without requiring additional subunits. The isolated CHD1 ATPase is sufficient to reposition nucleosomes in vitro. This has made CHD1 a valuable model system for studying the basic mechanism of ATP-dependent nucleosome sliding. CHD proteins also have a preference for nucleosomes containing the histone variant H3.3, which is enriched at actively transcribed genes and regulatory elements.
INO80 Family
The INO80 (Inositol Requiring 80) family includes the INO80 and SWR1 complexes. These are large assemblies that are unique among remodelers in that they contain subunits with homology to the RuvB DNA helicase, which is involved in DNA repair in bacteria. INO80 complexes are primarily involved in the exchange of histone variants—replacing canonical H2A with the variant H2A.Z—but they also possess nucleosome sliding activity.
INO80 complexes are particularly important for DNA double-strand break repair. They slide nucleosomes away from the site of a break, allowing repair factors to access the damaged DNA. INO80 also plays a role in transcription by regulating the positioning of nucleosomes at promoters. The sliding activity of INO80 is weaker than that of SWI/SNF or ISWI complexes, suggesting that its primary function is histone exchange rather than long-range nucleosome movement.
Experimental Evidence for Nucleosome Sliding
In Vitro Reconstitution Assays
The first direct evidence for nucleosome sliding came from in vitro reconstitution experiments. In a typical assay, a defined DNA fragment containing a strong nucleosome positioning sequence—such as the 601 sequence, which was selected for its high affinity for histone octamers—is assembled into mononucleosomes using purified histones. The resulting nucleosomes are then incubated with a remodeling complex and ATP, and the position of the nucleosome on the DNA is analyzed.
The classic readout for these experiments is a native gel electrophoresis assay. Nucleosomes that are positioned at different locations on the DNA fragment migrate at different rates through the gel because the shape and hydrodynamic properties of the nucleosome-DNA complex depend on the position of the octamer. By comparing the mobility of nucleosomes before and after incubation with a remodeler, researchers can directly observe sliding. These assays have demonstrated that remodeling complexes can slide nucleosomes to specific positions, often with a preference for locations that place the dyad at the center of the DNA fragment.
Single-Molecule FRET
Single-molecule Förster resonance energy transfer (FRET) has provided unprecedented insight into the dynamics of nucleosome sliding. In these experiments, a donor fluorophore is attached to one location on the DNA and an acceptor fluorophore to another location, such as on a histone protein. As the nucleosome slides, the distance between the two fluorophores changes, which alters the FRET efficiency. By monitoring FRET in real time, researchers can observe individual sliding events as they occur.
Single-molecule FRET studies have revealed that nucleosome sliding is not a smooth, continuous process. Instead, it occurs in discrete steps, with the nucleosome pausing at intermediate positions before moving again. These pauses often correspond to positions where the DNA sequence creates a local energy barrier. Single-molecule experiments have also directly visualized the formation of DNA bulges during ATP-dependent sliding, providing strong support for the loop-recapture model.
DNA Accessibility Assays
DNA accessibility assays measure the ability of enzymes or chemical probes to access DNA that is wrapped around a nucleosome. The most common approach uses restriction enzymes, which can only cut DNA at sites that are not occluded by the histone octamer. By designing DNA fragments with restriction sites at various positions relative to the nucleosome, researchers can map which regions of DNA are exposed and how this changes upon sliding.
A complementary approach uses DNase I, an endonuclease that cleaves DNA preferentially in regions that are accessible. When nucleosomes are positioned on a DNA fragment, DNase I digestion produces a characteristic ladder of fragments corresponding to the periodic exposure of DNA every 10–11 base pairs. Changes in this digestion pattern upon treatment with a remodeling complex provide evidence for nucleosome sliding. These assays have been used extensively to demonstrate that remodeling complexes can expose transcription factor binding sites by sliding nucleosomes away from them.
Methods to Study Nucleosome Sliding
Gel Mobility Shift Assay
The gel mobility shift assay (EMSA) is the most widely used method for detecting nucleosome sliding in vitro. The principle is simple: nucleosomes of different translational positions have different electrophoretic mobilities in a native polyacrylamide gel. This is because the position of the DNA ends relative to the histone octamer affects the overall shape and charge of the complex.
In a typical experiment, nucleosomes are assembled on a radiolabeled or fluorescently labeled DNA fragment. After incubation with a remodeling complex and ATP, the samples are loaded onto a 5–6% polyacrylamide gel and electrophoresed at 4°C. The gel is then imaged to visualize the positions of the nucleosome bands. Sliding is detected as a change in the mobility of the nucleosome band, often appearing as a ladder of bands corresponding to different nucleosome positions. This assay is rapid, quantitative, and can be used to measure the rate and directionality of sliding.
Restriction Enzyme Accessibility
Restriction enzyme accessibility assays provide a functional readout of nucleosome sliding. The assay exploits the fact that restriction enzymes cannot cut DNA that is wrapped around a histone octamer. By placing a restriction site at a specific position within the nucleosomal DNA, researchers can determine whether sliding has exposed that site.
The assay is performed by assembling nucleosomes on a DNA fragment containing a unique restriction site. The nucleosomes are then incubated with a remodeling complex and ATP, followed by digestion with the restriction enzyme. The extent of digestion is quantified by agarose gel electrophoresis, which separates the full-length DNA from the digested fragments. An increase in digestion indicates that the restriction site has become accessible due to nucleosome sliding. This assay is particularly useful for determining the direction of sliding, as it can distinguish between movement toward or away from a specific DNA element.
MNase-Seq
Micrococcal nuclease digestion followed by high-throughput sequencing (MNase-seq) is the gold standard for mapping nucleosome positions genome-wide. MNase is an endonuclease that preferentially cleaves DNA in the linker regions between nucleosomes, while the DNA wrapped around the histone octamer is protected from digestion. By sequencing the protected DNA fragments, researchers can determine the positions of nucleosomes across the entire genome.
MNase-seq can be used to study nucleosome sliding by comparing nucleosome positions between different conditions—for example, before and after treatment with a remodeling inhibitor, or between wild-type and mutant cells. Changes in the position of nucleosome peaks between conditions provide evidence for sliding. The resolution of MNase-seq is typically 10–20 base pairs, which is sufficient to detect most biologically relevant sliding events. However, it is important to note that MNase has some sequence bias, and the results should be validated with independent methods.
Cryo-Electron Microscopy
Cryo-electron microscopy (cryo-EM) has revolutionized the study of nucleosome remodeling by providing high-resolution structures of remodeling complexes bound to nucleosomes. In a typical cryo-EM experiment, the remodeling complex is incubated with a nucleosome and a non-hydrolyzable ATP analog such as AMP-PNP, which traps the complex in a catalytically relevant state. The sample is then rapidly frozen and imaged in a transmission electron microscope.
Cryo-EM structures have revealed how the ATPase motor of remodeling complexes engages with the nucleosome. The ATPase binds to the DNA at the entry site, and its translocation domain is positioned to pump DNA toward the dyad. The structures also show how the ATPase induces a bulge in the DNA, providing direct visual evidence for the loop-recapture model. Cryo-EM has also captured remodeling complexes in different conformational states, revealing the series of structural changes that occur during the ATP hydrolysis cycle.
Biological Consequences of Nucleosome Sliding
Regulation of Transcription
Nucleosome sliding is a primary mechanism for regulating transcription initiation. In the yeast Saccharomyces cerevisiae, the PHO5 gene provides a classic example. The PHO5 promoter contains two nucleosomes that are positioned over upstream activating sequences. When phosphate is limiting, the SWI/SNF complex is recruited to the promoter and slides these nucleosomes away, exposing the activator binding sites. This allows the Pho4 transcription factor to bind and activate transcription. The sliding event is rapid and reversible, demonstrating how nucleosome positioning can dynamically control gene expression.
In higher eukaryotes, nucleosome sliding is equally important. At many promoters, a nucleosome is positioned directly over the transcription start site (TSS). This "-1 nucleosome" must be slid upstream or downstream for RNA polymerase II to initiate transcription. The ISWI and CHD families of remodelers are particularly important for this process. Additionally, nucleosome sliding at enhancers can regulate the binding of transcription factors that control cell-type-specific gene expression programs.
DNA Replication and Repair
Nucleosome sliding also plays critical roles in DNA replication and repair. During replication, the replication fork must traverse chromatin, and nucleosomes ahead of the fork must be disassembled to allow the DNA polymerase to access the template. Behind the fork, nucleosomes are reassembled and must be properly positioned. ISWI and CHD remodelers are involved in this post-replicative nucleosome assembly, ensuring that nucleosomes are correctly spaced on the newly synthesized DNA.
In DNA repair, nucleosome sliding is essential for accessing damaged DNA. When a double-strand break occurs, the INO80 complex is recruited to the break site and slides nucleosomes away, creating a region of accessible DNA where repair factors can bind. Similarly, during nucleotide excision repair, the SWI/SNF complex slides nucleosomes to expose the damaged bases. After repair is complete, nucleosomes must be slid back to their original positions to restore the chromatin structure. Defects in this process can lead to genomic instability and cancer.
Common Pitfalls and Misconceptions
Sliding vs. Histone Eviction
A common error is to conflate nucleosome sliding with histone eviction. Sliding involves the movement of an intact histone octamer along the DNA, whereas eviction involves the complete removal of the octamer from the DNA, resulting in a nucleosome-free region. These are distinct outcomes mediated by different mechanisms. SWI/SNF complexes are capable of both sliding and eviction, but the choice between these outcomes depends on the specific context, including the DNA sequence, the presence of histone modifications, and the availability of histone chaperones.
To distinguish between sliding and eviction experimentally, researchers use assays that detect the presence of the histone octamer. For example, a gel shift assay can distinguish between a nucleosome (which migrates slowly) and free DNA (which migrates quickly). If the nucleosome band shifts to a new position but remains intact, sliding has occurred. If the nucleosome band disappears and free DNA appears, eviction has occurred.
ATP-Dependence Misconception
Another misconception is that nucleosome sliding always requires ATP. While ATP-dependent remodeling is the dominant mechanism in cells, spontaneous sliding can occur in the absence of ATP. This is driven by thermal energy and is particularly relevant for nucleosomes on flexible DNA sequences. In vitro, spontaneous sliding can be observed by incubating nucleosomes at elevated temperatures (37–42°C) for extended periods (hours to days). The rate of spontaneous sliding is much slower than ATP-dependent sliding, but it is nonetheless a real phenomenon.
It is also important to note that ATP is required for the activity of remodeling complexes, but the ATP is not used to directly "push" the nucleosome. Instead, ATP hydrolysis drives conformational changes in the ATPase motor, which then generates the mechanical force that moves the nucleosome. The energy from ATP hydrolysis is used to overcome the energy barriers associated with breaking histone-DNA contacts.
Nucleosome Positioning Sequence Preferences
Students often assume that nucleosomes bind to DNA randomly and that sliding is the only determinant of nucleosome position. In reality, the DNA sequence itself has a strong influence on nucleosome positioning. Certain sequences, such as the 601 sequence, have a very high affinity for histone octamers and position nucleosomes with high precision. These sequences are characterized by periodic occurrences of AT dinucleotides that facilitate DNA bending.
Genome-wide, nucleosome positioning is influenced by the underlying DNA sequence, with a preference for nucleosomes to be depleted from GC-rich regions and enriched in AT-rich regions. This sequence preference is not absolute, and ATP-dependent remodelers can override it, but it provides a baseline landscape that remodelers act upon. Understanding this interplay between sequence preferences and active remodeling is essential for predicting nucleosome positions in any given genomic region.
Summary and Study Tips
Key Takeaways
- Nucleosome sliding is the movement of an intact histone octamer along DNA, distinct from histone eviction or exchange.
- Spontaneous sliding occurs via thermal fluctuations, but ATP-dependent remodeling complexes catalyze the vast majority of sliding in cells.
- The two principal mechanisms of sliding are the twist-defect model and the loop-recapture model, both of which involve the propagation of a DNA perturbation around the histone octamer.
- Major remodeling complex families—SWI/SNF, ISWI, CHD, and INO80—have distinct roles in sliding, spacing, and histone exchange.
- Nucleosome sliding is experimentally studied using gel shift assays, restriction enzyme accessibility, MNase-seq, and cryo-EM.
- Sliding regulates transcription, replication, and repair by controlling DNA accessibility.
Exam Preparation Tips
When studying nucleosome sliding, focus on understanding the energetic principles rather than memorizing every detail. Draw diagrams of the nucleosome and trace how a twist defect or a DNA loop would propagate around the octamer. Practice explaining the difference between sliding, eviction, and exchange in your own words. For the remodeling complexes, create a table comparing their ATPase subunits, associated proteins, and primary functions. Finally, work through the experimental methods and ask yourself what each assay can and cannot tell you about nucleosome dynamics.
Frequently Asked Questions
What is nucleosome sliding?
Nucleosome sliding is the process by which a histone octamer moves laterally along the DNA molecule, changing the position of the nucleosome relative to the underlying DNA sequence. The histone octamer remains intact during sliding, and the total length of DNA wrapped around it (approximately 147 base pairs) does not change. Sliding is a key mechanism for regulating DNA accessibility in chromatin.
What is the nucleosome sliding mechanism?
Nucleosome sliding occurs through two principal mechanisms. In the twist-defect model, a local perturbation in DNA twist propagates around the histone octamer, shifting the register of histone-DNA contacts by one base pair at a time. In the loop-recapture model, a bulge of DNA forms at the entry site, travels around the octamer, and is recaptured at the exit site, moving the nucleosome by 10–50 base pairs in a single event. Both mechanisms can occur spontaneously, but ATP-dependent remodeling complexes accelerate them by actively generating the necessary DNA perturbations.
Does nucleosome sliding require ATP?
Nucleosome sliding can occur without ATP through thermal fluctuations, but this spontaneous sliding is slow and inefficient. In cells, the vast majority of regulated sliding is catalyzed by ATP-dependent chromatin remodeling complexes, which use the energy from ATP hydrolysis to actively reposition nucleosomes. The ATP is used by the ATPase motor of the remodeler to generate mechanical force, not to directly push the nucleosome.
What are chromatin remodeling complexes?
Chromatin remodeling complexes are multi-subunit enzymes that use ATP hydrolysis to alter nucleosome structure and position. They are classified into four major families—SWI/SNF, ISWI, CHD, and INO80—based on the sequence of their ATPase subunit. These complexes slide nucleosomes, evict histones, exchange histone variants, and space nucleosomes, thereby controlling DNA accessibility for transcription, replication, and repair.
How is nucleosome sliding studied experimentally?
Nucleosome sliding is studied using a combination of biochemical and biophysical methods. Gel mobility shift assays detect changes in nucleosome position based on electrophoretic mobility. Restriction enzyme accessibility assays measure the exposure of specific DNA sites. MNase-seq maps nucleosome positions genome-wide. Single-molecule FRET and cryo-EM provide real-time and structural information about the sliding mechanism.
Why is nucleosome sliding important?
Nucleosome sliding is important because it controls the accessibility of DNA to the cellular machinery. By repositioning nucleosomes, cells can expose or occlude transcription factor binding sites, promoters, enhancers, origins of replication, and sites of DNA damage. This makes sliding a central mechanism for regulating gene expression, DNA replication, and genome stability.
What is the difference between nucleosome sliding and remodeling?
Nucleosome sliding is a specific type of chromatin remodeling. Remodeling is a broader term that encompasses all ATP-dependent changes to nucleosome structure, including sliding, histone eviction, histone exchange, and changes in nucleosome spacing. Sliding specifically refers to the lateral movement of an intact histone octamer along the DNA, without any change in the histone composition or the total length of wrapped DNA.
Key Takeaways
- Nucleosome sliding is the lateral movement of an intact histone octamer along DNA, distinct from eviction or exchange.
- Spontaneous sliding occurs via thermal fluctuations, but ATP-dependent remodeling complexes catalyze most sliding in cells.
- The twist-defect and loop-recapture models describe the two principal mechanisms of sliding.
- SWI/SNF, ISWI, CHD, and INO80 are the four major families of chromatin remodeling complexes.
- Sliding is studied using gel shift assays, restriction enzyme accessibility, MNase-seq, single-molecule FRET, and cryo-EM.
- Sliding regulates transcription, replication, and repair by controlling DNA accessibility.
- Sequence preferences and histone modifications modulate the rate and direction of sliding.
Further Reading
- Bowman GD. Mechanisms of ATP-dependent nucleosome sliding. Current opinion in structural biology. 2010. PubMed 20060707
- Becker PB. Nucleosome sliding: facts and fiction. The EMBO journal. 2002. PubMed 12234915
- Mueller-Planitz F, Klinker H, Becker PB. Nucleosome sliding mechanisms: new twists in a looped history. Nature structural & molecular biology. 2013. PubMed 24008565
- Vizjak P et al. ISWI catalyzes nucleosome sliding in condensed nucleosome arrays. Nature structural & molecular biology. 2024. PubMed 38664566
- Kadam S, Bameta T, Padinhateeri R. Nucleosome sliding can influence the spreading of histone modifications. Physical review. E. 2022. PubMed 36110002
- Vizjak P et al. ISWI catalyzes nucleosome sliding in condensed nucleosome arrays. bioRxiv : the preprint server for biology. 2023. PubMed 38106060