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Energy-driven genome regulation by ATP-dependent chromatin remodellers

Nature Reviews Molecular Cell Biology volume 25, pages 309–332 (2024)Cite this article

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Abstract

The packaging of DNA into chromatin in eukaryotes regulates gene transcription, DNA replication and DNA repair. ATP-dependent chromatin remodelling enzymes (re)arrange nucleosomes at the first level of chromatin organization. Their Snf2-type motor ATPases alter histone–DNA interactions through a common DNA translocation mechanism. Whether remodeller activities mainly catalyse nucleosome dynamics or accurately co-determine nucleosome organization remained unclear. In this Review, we discuss the emerging mechanisms of chromatin remodelling: dynamic remodeller architectures and their interactions, the inner workings of the ATPase cycle, allosteric regulation and pathological dysregulation. Recent mechanistic insights argue for a decisive role of remodellers in the energy-driven self-organization of chromatin, which enables both stability and plasticity of genome regulation — for example, during development and stress. Different remodellers, such as members of the SWI/SNF, ISWI, CHD and INO80 families, process (epi)genetic information through specific mechanisms into distinct functional outputs. Combinatorial assembly of remodellers and their interplay with histone modifications, histone variants, DNA sequence or DNA-bound transcription factors regulate nucleosome mobilization or eviction or histone exchange. Such input–output relationships determine specific nucleosome positions and compositions with distinct DNA accessibilities and mediate differential genome regulation. Finally, remodeller genes are often mutated in diseases characterized by genome dysregulation, notably in cancer, and we discuss their physiological relevance.

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Fig. 1: Active chromatin self-organization and genome regulation.
Fig. 2: Nucleosome organization by remodellers.
Fig. 3: Assemblies and architectures of chromatin remodellers.
Fig. 4: Nucleosome binding and DNA translocation mechanism of Snf2-type motor ATPases.
Fig. 5: Structural mechanisms and principles of remodelling.
Fig. 6: Three stages of nucleosome remodelling and an updated hourglass model.
Fig. 7: Examples of input–output relationships provided by remodellers.
Fig. 8: Cancer mutations affect chromatin remodellers in various ways.

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Acknowledgements

Animations were created by G. Hsu and J. Iwasa based on many enjoyable and insightful discussions. We gratefully acknowledge input from colleagues, especially from G. Narlikar on energetics of remodeller mechanisms, D. Herschlag on coupled vectorial processes, J.s Buchner and F. U. Hartl on molecular chaperones, R. Louder on remodeller compositions and P. Becker on remodellers by and large. This work was funded by NIGMS (R01GM135651 and R01GM144559 to Y.H.), the German Research Foundation (SFB/CRC1064 ‘Chromatin dynamics’ to P.K. and K.P.H.) and the European Molecular Biology Laboratory (S.E.). We especially appreciate cofunding the costs of generating animations by the German Research Foundation’s grant SFB/CRC1064 to P.K. and K.-P.H.

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Author notes

  1. These authors contributed equally: Sebastian Eustermann, Avinash B. Patel.

Authors and Affiliations

  1. Structural and Computational Biology Unit, European Molecular Biology Laboratory (EMBL), Heidelberg, Germany

    Sebastian Eustermann

  2. Department of Molecular Biosciences, Robert H. Lurie Comprehensive Cancer Center, Chemistry of Life Processes Institute, Northwestern University, Evanston, IL, USA

    Avinash B. Patel & Yuan He

  3. Gene Center and Department of Biochemistry, Faculty of Chemistry and Pharmacy, LMU Munich, Munich, Germany

    Karl-Peter Hopfner

  4. Biomedical Center (BMC), Molecular Biology, Faculty of Medicine, LMU Munich, Martinsried, Germany

    Philipp Korber

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COSMIC: https://cancer.sanger.ac.uk/cosmic

Supplementary information

41580_2023_683_MOESM1_ESM.mp4

Supplementary Video 1. Nucleosome organization by ATP-dependent chromatin remodellers at gene promoters. Inside the nucleus, wrapping of DNA around histone proteins forms nucleosomes. Nucleosomes have some intrinsic flexibility but cannot move along much or leave the DNA without ATP-dependent chromatin remodellers. Chromatin remodellers come in different types, mostly large multisubunit complexes, but some are monomers. Their signature feature is a motor ATPase, highlighted in red that converts ATP hydrolysis energy into nucleosome remodelling. The remodelling outcome is remodeller-specific as remodellers differ in their intrinsic and context-dependent recruitment, regulation and release mechanisms. Here we show how the cooperation between remodeller-specific activities shapes nucleosome architecture of yeast promoters and genes. No strict temporal order of remodellers' activities is implied and remodellers may also work in parallel. Nucleosomes restrict access to DNA. Here, a gene promoter, marked in red, is part of a nucleosome and therefore inaccessible. Certain chromatin remodellers, such as RSC from yeast, can disassemble nucleosomes by histone eviction. This generates a nucleosome-free region with accessible DNA. Such accessible DNA can be bound by sequence-specific DNA-binding factors that may help establish and maintain the nucleosome-free region as well as serve as reference points, also called boundaries or barriers, for nucleosome positioning. Some remodellers, like the INO80 complex, are able to position nucleosomes relative to such barriers or to neighbouring nucleosomes or to DNA sequence features. In this case, INO80 determines the position of the first nucleosome downstream of the promoter, the so-called +1 nucleosome, relative to the barrier protein and likely also according to DNA sequence properties underlying the +1 nucleosome position. SWR1 is a histone exchanger, another type of chromatin remodeller. SWR1 releases a canonical histone H2A–H2B dimer and replaces it with a variant H2A.Z–H2B dimer. Several remodeller types, for example members of the ISWI family, reposition nucleosomes relative to neighbouring nucleosomes. This spacing activity generates arrays of evenly spaced nucleosomes, a conserved hallmark of chromatin. The coordinated remodeller-specific activities generate a nucleosome organization at the promoter that is conducive for transcription. RNA polymerase, together with other transcription factors that are not shown, assembles at the promoter and transcribes the gene. This disrupts nucleosomes and array regularity. Remodellers, such as Chd1, aid in transcription through nucleosomes and restoration of the regular array.

41580_2023_683_MOESM2_ESM.mp4

Supplementary Video 2. Architecture and mechanisms of the SWI/SNF-family remodeller RSC. The SWI/SNF family comprises multisubunit chromatin remodellers composed of a rigid core that tethers a flexible motor ATPase, the tail and ARP modules and various other smaller domains that recognize DNA and histone marks. RSC, a member of the SWI/SNF remodeller family in yeast, is responsible for maintaining nucleosome-free regions by nucleosome disassembly from gene promoters. RSC’s bromodomains bind to acetylated histone H3 tails of the nucleosome, whereas the Sfh1 helix binds to the acidic patch on the nucleosome side where DNA exits during remodelling. In addition, the SnAC domain of the ATPase subunit binds to the entry side acidic patch of the nucleosome. Next, the motor ATPase domain engages the nucleosome. During nucleosome remodelling, the RSC core and the SnAC domain bind the histone octamer while the ATPase translocates the DNA. The motor ATPase remodels the nucleosome in one base pair steps, causing the DNA to be translocated relative to the histone octamer, maybe with asynchrony between entry and exit side, leading in the end to nucleosome sliding. As described first for INO80, motor, rotor, stator and grip elements can be identified in analogy to electric motors. These may ensure that the motor ATPase remains in place and can break histone–DNA contacts. Thereby, RSC activity may achieve eviction of histones. Either sliding or eviction can expose promoter DNA.

41580_2023_683_MOESM3_ESM.mp4

Supplementary Video 3. Architecture and mechanisms of the INO80-family remodeller INO80. The 15-subunit yeast INO80 complex comprises three modules: the core module, the Arp-module and a species-specific Nhp10 module. The core module remodels nucleosomes, like promoter +1 nucleosomes, while the Arp- and Nhp10 modules sense adjacent free DNA. The complex is named after its Ino80 subunit, highlighted here in red and also shown schematically. It harbours the motor ATPase, is a scaffold for assembly and mediates regulation of all three modules. The Ino80 N terminus assembles the Nhp10 module. The central HSA domain binds DNA and the Arp module subunits. The post-HSA domain regulates the motor ATPase. DNA recognition by the Arp module allosterically controls the remodelling activity. The Ino80 motor ATPase has a long insertion, which is captured in the central chamber of the hexameric Rvb1/2 ring. This assembly is a recruitment platform for other subunits and determines how the core module clasps and remodels the nucleosome. The DNA is bound at the entry side by the motor ATPase and on the opposite side by Arp5. The histone octamer is bound at the entry as well as exit side acidic patches. The way INO80 and other multisubunit remodellers bind to the nucleosome suggests motor, rotor, stator and grip elements similar to the functional elements of electric motors. Fuelled by ATP hydrolysis, the motor ATPase rotates the entry DNA relative to the Rvb1/2 stator. Coupling of this stator to the Arp5 grip ensures that the motor stays in place while DNA is translocated. Successive rounds of step-wise translocation may underwind DNA and build up strain against the Arp5 grip. The response to such strain depends on sequence-specific mechanics of tilting, rolling, twisting, shifting and sliding of the DNA base pairs. If sufficient DNA strain can be generated, a wave of multiple DNA base pairs may propagate beyond the Arp5 grip around the histone octamer. A series of such DNA translocation steps can result in large nucleosome sliding steps. Transient destabilization of DNA contacts to histone H2A and H2B may explain other remodelling outcomes such as histone exchange. The ratchet-like remodelling linked to sensing promoter DNA by the Arp module may translate DNA sequence mechanics into +1 nucleosome positioning by INO80. Overall, INO80 works like a hub where input information from the DNA sequence, histone modifications, nucleosome neighbours and other factors is processed through its intrinsic mechanism into a functional output.

41580_2023_683_MOESM4_ESM.mp4

Supplementary Video 4. Architecture and mechanism of the CHD-family remodeller Chd1. Chd1 is a monomeric chromatin remodeller that is primarily involved in maintaining regular arrays in transcribed regions. Chd1 has three domains: tandem chromodomains, a motor ATPase and a DNA-binding domain. The N-terminal ChEx motif functions to block opposing remodellers by direct association with the histone core. Chd1 has been shown to bind the nucleosome involving a 15-degree swinging movement of the double chromodomains. In addition, DNA can be peeled from the histone octamer. The mechanistic role of this is still unclear, but in the end the ATPase closes and is activated. The ratcheting movement of the ATPase induces a local A-form DNA geometry, allowing its translocation towards the nucleosome dyad. The location of the DNA-binding domain is not shown during active DNA translocation by Chd1 as it is currently debated if the DNA-binding domain then binds to the exit or entry DNA.

Supplementary Information

Glossary

3D–1D diffusion model of transcription factors

Classical model describing how transcription factors find their genomic binding sites by a combination of 3D diffusion between stretches of DNA and 1D diffusion along the DNA.

ATPase fold

Evolutionarily conserved protein fold that confers ATP binding and hydrolysis activity.

Barrier

Alignment points on the DNA that enable array phasing and often correspond to sequence-specific DNA-binding proteins but may also consist of a nucleosome itself or a DNA end.

CCCTC-binding factor

(CTCF) A ubiquitously expressed, essential and highly conserved protein in mammals that modulates chromatin architecture, for example in loop extrusion by cohesins.

Chromatin states

Different compositions and configurations of chromatin, including DNA methylation, that regulate genome functions such as regulating transcription and DNA replication.

DNA shape and mechanics

The DNA sequence specifies DNA mechanical properties both of the ground-state (DNA shape) and during dynamic distortions, for example, during DNA tracking by helicases, polymerases or remodellers.

Entry DNA

Nucleosome DNA that is moved towards the dyad during ATP-dependent remodelling.

Epigenetic regulation

Stable and sometimes heritable regulation of genome activities through differential chromatin states without alterations of the DNA sequence.

Exit DNA

Nucleosome DNA that is moved away from the dyad during ATP-dependent remodelling.

H2A–H2B acidic patch

Negatively charged surface patch of the histone H2A–H2B dimer, which serves as a binding platform where various chromatin factors bind the histone core.

Histone elbow

First helix and loop of histone H3 and H2B, which serve as a binding platform where various chromatin factors bind the histone core.

Lowered entropy

According to the second law of thermodynamics, if a system becomes more defined (‘ordered’) its entropy is lowered and its free energy is increased.

Noncanonical nucleosomal particles

Particles that differ from canonical nucleosomes in their histone stoichiometry, structural plasticity and mode of DNA wrapping.

Nucleosome organization

The compositions and positions of nucleosomes along the genome, including noncanonical nucleosomal particles.

Phased

Nucleosome arrays are phased if in many DNA molecules (for example, in a cell population) they begin at the same (for example, a certain genomic coordinate) or at an analogous position (for example, at the same distance to the TSS).

Pseudo-two-fold symmetry dyad axis

The axis along an NCP can have a twofold rotational symmetry, even though the DNA sequence usually breaks the symmetry.

Self-assembly

Refers to the association of constituents, according to constituent-intrinsic properties, into a structure at equilibrium, for example, a native protein structure or a nucleic acid double helix.

Self-organization

Constituents become organized according to local and constituent-intrinsic properties and without global ‘template’ or ‘blueprint’ information into a dynamic steady-state that continuously undergoes turnover and requires net energy flux.

Spaced nucleosomes

Nucleosome spacing refers to the distance between NCPs, that is the length of linker DNA.

Subsite

Part of a binding site to which a particular functionality can be assigned, for example containing a sequence motif or being involved in ligand recognition.

Twist

Describes the angle of rotation around the DNA double helix axis from one base pair to the next along a DNA duplex.

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Eustermann, S., Patel, A.B., Hopfner, KP. et al. Energy-driven genome regulation by ATP-dependent chromatin remodellers. Nat Rev Mol Cell Biol 25, 309–332 (2024). https://doi.org/10.1038/s41580-023-00683-y

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