GO:0140658 ATP-dependent chromatin remodeler activity: Mechanism, Genes and Research Methods
Research-grade guide for scientists and biopharma professionals
Key Takeaways
• GO:0140658 ATP-dependent chromatin remodeler activity is a molecular function that uses ATP hydrolysis to alter histone-DNA contacts and remodel nucleosomal arrays.
• This activity is carried out by multi-subunit complexes such as SWI/SNF, ISWI, CHD, and INO80, which share a conserved ATPase motor but differ in accessory subunits and biological roles.
• ATP-dependent chromatin remodelers regulate transcription, DNA replication, DNA repair, and recombination by controlling nucleosome positioning and chromatin accessibility.
• Mutations in remodeler subunits, especially SMARCA4 and ARID1A, are frequent in cancers and are linked to poor prognosis and potential therapeutic vulnerabilities.
• Loss of remodeler function causes developmental disorders, including inner ear defects and intellectual disability syndromes.
• CRISPR-based knockout, point mutation, knock-in, and overexpression models are essential for dissecting the causal roles of remodeler genes in disease and development.
Description
ATP-dependent chromatin remodeler activity (GO:0140658) is a fundamental molecular function that enables cells to dynamically reorganize chromatin architecture. This activity is driven by ATP hydrolysis and results in changes in the contacts between histones and DNA within nucleosomal arrays, thereby controlling access to the genetic material. Chromatin remodelers are essential for virtually all DNA-templated processes, including transcription, replication, DNA repair, and recombination. Because of their central role in genome regulation, mutations in remodeler genes are associated with a wide range of human diseases, particularly cancer and developmental disorders. Researchers studying this activity seek to understand how remodelers are targeted to specific genomic loci, how their catalytic cycles are regulated, and how their dysfunction contributes to disease. This article provides a comprehensive overview of the definition, mechanism, key genes, disease links, and experimental approaches for studying ATP-dependent chromatin remodeler activity, with a focus on CRISPR-based models and modern genomic methods.
ATP-dependent chromatin remodeler activity At A Glance
| GO ID | GO:0140658 |
|---|---|
| GO term | ATP-dependent chromatin remodeler activity |
| Ontology | molecular_function |
| Definition | An activity, driven by ATP hydrolysis, that modulates the contacts between histones and DNA, resulting in a change in chromosome architecture within the nucleosomal array, leading to chromatin remodeling. |
| Synonyms | ATPase-dependent chromatin remodeler activity; ATP-dependent chromatin remodeller activity; ATP-dependent chromatin remodelling; ATP hydrolysis-dependent chromatin remodeler activity; nucleosome-activated ATPase activity; nucleosome-dependent ATPase activity |
| Major function | ATP hydrolysis-driven reorganization of nucleosomes to regulate DNA accessibility. |
| Representative complexes | SWI/SNF, ISWI, CHD, INO80. |
| Cofactors | ATP, nucleosomes, and accessory subunits. |
| Related diseases | Cancer, developmental disorders, inner ear defects. |
What Is GO:0140658?
According to the Gene Ontology, ATP-dependent chromatin remodeler activity (GO:0140658) is defined as an activity, driven by ATP hydrolysis, that modulates the contacts between histones and DNA, resulting in a change in chromosome architecture within the nucleosomal array, leading to chromatin remodeling. In simpler terms, it is the energy-consuming process by which specialized protein machines slide, eject, or restructure nucleosomes to make DNA more or less accessible to other nuclear factors.
Why Is ATP-dependent chromatin remodeler activity Important in Cell Biology?
ATP-dependent chromatin remodeler activity is essential for the dynamic regulation of chromatin structure, which underpins gene expression, DNA replication, and genome stability. Dysregulation of this activity is a hallmark of many cancers and developmental syndromes, making it a high-priority target for basic and translational research. Understanding the molecular mechanisms of remodelers can inform the development of targeted therapies and CRISPR-based disease models.
• Controls nucleosome positioning and chromatin accessibility, thereby regulating gene expression programs.
• Essential for DNA replication, repair, and recombination, contributing to genome stability.
• Mutations in SWI/SNF subunits such as SMARCA4 and ARID1A are frequent in multiple cancer types.
• Remodeler dysfunction causes developmental disorders, including inner ear malformations and intellectual disability.
• Plays a key role in resolving transcription-replication conflicts and R-loop-mediated genome instability.
• Involved in the regulation of chromatin condensates and mesoscale chromatin organization.
• Provides potential therapeutic targets for cancers with remodeler mutations.
• Serves as a paradigm for studying energy-driven genome regulation.
• Enables the study of chromatin dynamics using advanced imaging and genomics methods.
• CRISPR screens can identify synthetic lethal interactions with remodeler loss.
Core Mechanisms of ATP-dependent chromatin remodeler activity
What Happens During ATP-dependent chromatin remodeler activity?
In simple terms: Chromatin remodelers use energy from ATP to slide or eject nucleosomes, changing which parts of DNA are accessible.
ATP-dependent chromatin remodelers bind to nucleosomes and, upon ATP hydrolysis, alter histone-DNA contacts to reposition, eject, or restructure nucleosomes. This process is fundamental for regulating access to DNA during transcription, replication, and repair. The activity is highly dynamic and can lead to either chromatin opening or compaction, depending on the remodeler complex and its associated factors.
Nucleosome Recognition and Binding
In simple terms: Remodelers first attach to nucleosomes, the DNA-protein spools that package DNA.
Remodeler complexes recognize specific histone modifications and DNA sequences to target nucleosomes. The ATPase motor domain engages the nucleosome at the superhelical location 2 (SHL2), a critical contact point for ATP-dependent remodeling. Accessory subunits and disordered regions further modulate binding specificity and condensation.
ATP Hydrolysis and DNA Translocation
In simple terms: The remodeler burns ATP to pull DNA around the histone core, like a motor pulling a rope.
ATP hydrolysis drives conformational changes in the ATPase domain that translocate DNA along the histone octamer surface. This translocation can result in nucleosome sliding, histone eviction, or exchange of histone variants. The energy from ATP is used to disrupt histone-DNA contacts and to generate a remodeled nucleosome state.
Chromatin Remodeling Outcomes
In simple terms: The result is a change in chromatin structure that can turn genes on or off.
Depending on the remodeler and context, remodeling can lead to nucleosome sliding, ejection, or spacing changes that alter chromatin accessibility. These outcomes affect transcription factor binding, RNA polymerase activity, and DNA repair. Recent studies show that remodelers can also reorganize chromatin condensates, affecting mesoscale chromatin architecture.
Structure and Composition of ATP-dependent chromatin remodeler activity
In simple terms: Remodelers are molecular machines made of many protein parts that work together.
ATP-dependent chromatin remodelers are multi-subunit complexes built around a conserved ATPase motor. Major families include SWI/SNF, ISWI, CHD, and INO80, each with distinct accessory subunits that confer specific functions. For example, the SWI/SNF complex contains a catalytic ATPase (SMARCA4 or SMARCA2) and multiple regulatory subunits such as ARID1A and SMARCB1. These complexes can form larger assemblies, such as the cBAF complex, which is regulated by disordered regions and condensation.
Molecular Mechanism of ATP-dependent chromatin remodeler activity
In simple terms: The motor domain uses ATP to change shape and move DNA, while other parts control when and where this happens.
The catalytic mechanism involves ATP binding to the ATPase domain, hydrolysis, and subsequent conformational changes that drive DNA translocation. Cofactors such as nucleosomes and specific histone modifications regulate the activity. Regulation occurs through subunit composition, post-translational modifications, and interaction with partner proteins. For instance, the disordered region of ARID1A controls cBAF activity via condensation and partner recruitment.
Key Genes Involved in GO:0140658 ATP-dependent chromatin remodeler activity
The following genes encode subunits or regulators of ATP-dependent chromatin remodeler complexes and are frequently studied in the context of GO:0140658.
| Gene | Major Role | Research Relevance |
|---|---|---|
| SMARCA4 | Catalytic ATPase subunit of SWI/SNF (BAF) complex | Frequently mutated in non-small-cell lung cancer and other cancers |
| SMARCA2 | Catalytic ATPase subunit of SWI/SNF, alternative to SMARCA4 | Synthetic lethal target in SMARCA4-deficient cancers |
| ARID1A | Non-catalytic subunit of SWI/SNF, involved in targeting and condensation | Mutations in ovarian clear cell carcinoma and other cancers |
| ARID1B | Subunit of SWI/SNF, paralog of ARID1A | Implicated in developmental disorders and cancer |
| SMARCB1 | Core subunit of SWI/SNF complex | Loss causes malignant rhabdoid tumors |
| CHD1 | Chromodomain helicase DNA-binding protein, ATPase | Prostate cancer and chromatin remodeling |
| CHD4 | ATPase subunit of NuRD complex | Regulates transcription and DNA repair |
| CHD7 | ATPase involved in chromatin remodeling | Mutations cause CHARGE syndrome |
| INO80 | Catalytic ATPase of INO80 complex | DNA repair and replication |
| SMARCA5 | ATPase subunit of ISWI complex | Chromatin assembly and replication |
| BAZ1A | Accessory subunit of ISWI complexes | Regulation of chromatin structure |
| BAZ1B | Subunit of ISWI complex | Williams-Beuren syndrome |
| BAZ2A | Subunit of NoRC complex | rRNA transcription regulation |
| BRD7 | Subunit of SWI/SNF complex | Transcriptional regulation |
| BRD9 | Subunit of ncBAF complex | Cancer dependencies |
| PBRM1 | Subunit of SWI/SNF complex | Renal cell carcinoma |
| ACTL6A | Actin-related protein in SWI/SNF | Chromatin remodeling and cancer |
| BCL7A | Subunit of SWI/SNF complex | Lymphoma and development |
How Is ATP-dependent chromatin remodeler activity Regulated?
ATP-dependent chromatin remodeler activity is regulated at multiple levels. Subunit composition determines targeting and activity; for example, the incorporation of ARID1A versus ARID1B alters complex stability and genomic localization. Post-translational modifications of subunits, such as phosphorylation and acetylation, can modulate activity. Interaction with transcription factors and non-coding RNAs recruits remodelers to specific loci. Additionally, the disordered regions of subunits can drive liquid-liquid phase separation, forming condensates that regulate remodeler activity and partner recruitment. ATP availability and nucleosome density also influence activity.
ATP-dependent chromatin remodeler activity and Human Disease
| Gene | Disease / Biology | Potential Experimental Model |
|---|---|---|
| SMARCA4 | Non-small-cell lung cancer | Knockout and point mutation in lung cancer cell lines |
| ARID1A | Ovarian clear cell carcinoma | Knockout and knock-in of mutant ARID1A in ovarian cells |
| CHD7 | CHARGE syndrome | Knockout and point mutation in iPSC-derived inner ear organoids |
| SMARCB1 | Malignant rhabdoid tumor | Knockout in rhabdoid tumor cell lines |
| PBRM1 | Renal cell carcinoma | Knockout in renal cancer cells |
Cancer
Mutations in ATP-dependent chromatin remodeler genes are among the most common alterations in human cancers. SMARCA4 is frequently mutated in non-small-cell lung cancer, where loss of function contributes to tumorigenesis and may create vulnerabilities to targeted therapies. ARID1A mutations are prevalent in ovarian clear cell carcinoma and other tumor types, and the disordered region of ARID1A controls cBAF complex activity, affecting cancer cell proliferation. SWI/SNF complex mutations are also found in renal cell carcinoma (PBRM1) and malignant rhabdoid tumors (SMARCB1).
Developmental Disorders
ATP-dependent chromatin remodelers are critical for development. Mutations in CHD7 cause CHARGE syndrome, characterized by inner ear defects and multiple congenital anomalies. Other remodeler genes, such as ARID1B and SMARCB1, are linked to intellectual disability and Coffin-Siris syndrome. The essential role of remodelers in inner ear development highlights their importance in sensory organ formation.
Genome Instability and Neurological Disease
Remodelers help resolve R-loop-mediated transcription-replication conflicts, and their loss leads to DNA damage and genome instability. This can contribute to neurodegenerative diseases and premature aging. Additionally, remodeler dysfunction affects neuronal gene expression programs, linking chromatin remodeling to neurological disorders.
From ATP-dependent chromatin remodeler activity-Related Genes to Experimental Models
| Research Question | Suitable Model |
|---|---|
| Does loss of SMARCA4 drive lung cancer growth? | SMARCA4 knockout in NSCLC cell lines and mouse models |
| How do ARID1A mutations affect cBAF condensation? | ARID1A point mutation and knockout in cancer cells |
| What is the role of CHD7 in inner ear development? | CHD7 knockout in iPSC-derived inner ear organoids |
| Can SMARCA2 be targeted in SMARCA4-deficient tumors? | SMARCA2 knockout or overexpression in SMARCA4-mutant cells |
| How does INO80 contribute to DNA repair? | INO80 knockout and tagged knock-in in U2OS cells |
| Does remodeler loss cause R-loop accumulation? | Knockout of SWI/SNF subunits in HeLa cells |
How to Study the ATP-dependent chromatin remodeler activity Process
| Method | What It Measures | Typical Application |
|---|---|---|
| ATAC-seq | Chromatin accessibility | Assessing remodeler impact on open chromatin |
| MNase-seq | Nucleosome positioning | Mapping nucleosome sliding by remodelers |
| ChIP-seq | Protein-DNA binding | Localizing remodeler subunits and histone marks |
| RNA-seq | Gene expression | Transcriptional changes after remodeler knockout |
| Proteomics | Protein interactions | Identifying remodeler complex components |
| Single-molecule imaging | Dynamic remodeling events | Visualizing nucleosome sliding in real time |
| Cryo-EM | 3D structure | Determining remodeler-nucleosome interfaces |
| CRISPR screens | Gene essentiality and synthetic lethality | Finding targets in remodeler-mutant cancers |
Genomic and Epigenomic Methods
ATAC-seq and MNase-seq measure chromatin accessibility and nucleosome positioning, respectively, to assess remodeler activity. ChIP-seq for histone modifications and remodeler subunits identifies genomic binding sites. These methods are widely used to study how remodelers shape the chromatin landscape.
Transcriptomic and Proteomic Approaches
RNA-seq reveals gene expression changes upon remodeler perturbation. Proteomics and co-immunoprecipitation identify interacting partners and complex composition. These techniques help define the regulatory networks controlled by remodelers.
Imaging and Biophysical Assays
Single-molecule imaging and FRAP measure remodeler dynamics and chromatin condensation. Cryo-EM provides structural insights into remodeler-nucleosome interactions. These approaches reveal mechanistic details of ATP-dependent remodeling.
CRISPR Screens and Functional Genomics
Genome-wide CRISPR knockout screens identify genes that are synthetic lethal with remodeler mutations, such as SMARCA4. Focused screens can uncover regulators of remodeler activity and resistance mechanisms. These functional genomics tools are powerful for discovering therapeutic targets.
How CRISPR Can Be Used to Study GO:0140658 ATP-dependent chromatin remodeler activity
Knockout
CRISPR knockout of remodeler genes such as SMARCA4, ARID1A, or CHD7 enables the study of loss-of-function phenotypes in cancer and development. Knockout cell lines are used to assess proliferation, chromatin accessibility, and drug sensitivity.
Point Mutation
Introducing specific point mutations (e.g., in the ATPase domain of SMARCA4) via CRISPR base editing or HDR allows researchers to dissect catalytic versus non-catalytic functions. Such models are valuable for understanding disease-associated mutations.
Knock-in
Knock-in of tagged remodeler subunits (e.g., GFP or HA) facilitates imaging and proteomic studies. Knock-in of patient-derived mutations in iPSCs can model developmental disorders like CHARGE syndrome.
Overexpression
CRISPR activation (CRISPRa) or cDNA overexpression can elevate remodeler levels to study gain-of-function effects and oncogenic roles. Overexpression models help identify dosage-sensitive pathways.
How EDITGENE Supports ATP-dependent chromatin remodeler activity Research
Researchers studying ATP-dependent chromatin remodeler activity-related genes often need to determine whether a candidate gene is causally involved in a specific biological process or disease. EDITGENE provides a comprehensive suite of CRISPR-based services to generate precisely engineered cell models, enabling rigorous functional validation and therapeutic target discovery.
Contact EDITGENE today to design your custom CRISPR model for ATP-dependent chromatin remodeler activity research.
Frequently Asked Questions About ATP-dependent chromatin remodeler activity
What is ATP-dependent chromatin remodeler activity?
It is a molecular function (GO:0140658) that uses ATP hydrolysis to change histone-DNA contacts and remodel nucleosomes, thereby altering chromatin structure.
What genes are involved in ATP-dependent chromatin remodeler activity?
Key genes include SMARCA4, SMARCA2, ARID1A, ARID1B, SMARCB1, CHD1, CHD4, CHD7, INO80, and SMARCA5, among others.
What diseases are associated with ATP-dependent chromatin remodeler mutations?
Mutations are linked to cancers such as non-small-cell lung cancer and ovarian clear cell carcinoma, as well as developmental disorders like CHARGE syndrome.
How do ATP-dependent chromatin remodelers work?
They bind nucleosomes, hydrolyze ATP to translocate DNA, and slide or eject nucleosomes, thereby regulating DNA accessibility.
What are the main families of ATP-dependent chromatin remodelers?
The major families are SWI/SNF, ISWI, CHD, and INO80, each with distinct subunit compositions and functions.
How can I study ATP-dependent chromatin remodeler activity in the lab?
Common methods include ATAC-seq, MNase-seq, ChIP-seq, RNA-seq, proteomics, and CRISPR screens.
What is the role of SMARCA4 in cancer?
SMARCA4 is frequently mutated in non-small-cell lung cancer and other cancers, where loss of function contributes to tumorigenesis.
Can CRISPR be used to model remodeler mutations?
Yes, CRISPR knockout, point mutation, knock-in, and overexpression are widely used to model remodeler gene alterations.
What is the connection between remodelers and R-loops?
SWI/SNF remodelers help resolve R-loop-mediated transcription-replication conflicts, and their loss leads to genome instability.
How does ARID1A mutation affect chromatin remodeling?
ARID1A mutations disrupt cBAF complex activity and condensation, affecting chromatin remodeling and gene expression.
Conclusion
ATP-dependent chromatin remodeler activity (GO:0140658) is a central molecular function that governs chromatin architecture and genome regulation. Its dysregulation is implicated in cancer and developmental disorders, making it a critical area of research. Advances in CRISPR-based models and genomic technologies continue to unravel the mechanistic details and therapeutic potential of remodelers. EDITGENE provides the tools and expertise to accelerate discoveries in this field.
References
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