MaltSci 麦伴科研

Appearance

Popular Reports / Genomics

This report is written by MaltSci based on the latest literature and research findings

How does chromatin remodeling regulate gene expression? ​

Abstract ​

The regulation of gene expression is fundamental to numerous biological processes, including development, differentiation, and responses to environmental stimuli. Central to this regulation is chromatin remodeling, which alters the structure of chromatin, thus influencing the accessibility of transcriptional machinery to specific genomic regions. Chromatin remodeling complexes, such as SWI/SNF, ISWI, and CHD, utilize ATP hydrolysis to reposition nucleosomes, significantly impacting gene expression. Recent studies have highlighted the complex interactions between chromatin remodelers, transcription factors, and non-coding RNAs, revealing the dynamic nature of chromatin that can be influenced by various internal and external factors. This review provides an overview of chromatin structure, detailing nucleosome composition and higher-order chromatin organization, followed by an in-depth discussion of the mechanisms employed by major chromatin remodeling complexes. The impact of chromatin remodeling on gene expression is examined, focusing on gene activation and repression mechanisms, along with case studies illustrating its significance in development and disease, particularly cancer. The implications of chromatin remodeling in health and disease are explored, emphasizing its potential as a therapeutic target. By synthesizing recent findings, this review underscores the importance of chromatin dynamics in gene regulation and its potential for therapeutic intervention.

Outline ​

This report will discuss the following questions.

  • 1 Introduction
  • 2 Overview of Chromatin Structure
    • 2.1 Nucleosome Composition and Organization
    • 2.2 Higher-Order Chromatin Structures
  • 3 Chromatin Remodeling Complexes
    • 3.1 SWI/SNF Complex
    • 3.2 ISWI Complex
    • 3.3 CHD Complex
  • 4 Mechanisms of Chromatin Remodeling
    • 4.1 ATP-Dependent Remodeling
    • 4.2 Histone Modifications and Their Impact
    • 4.3 Interactions with Transcription Factors
  • 5 Role of Chromatin Remodeling in Gene Expression
    • 5.1 Activation of Gene Transcription
    • 5.2 Gene Repression Mechanisms
    • 5.3 Case Studies: Development and Disease
  • 6 Implications in Health and Disease
    • 6.1 Chromatin Remodeling in Cancer
    • 6.2 Potential Therapeutic Targets
  • 7 Conclusion

1 Introduction ​

The regulation of gene expression is a fundamental process that underlies numerous biological phenomena, including development, differentiation, and responses to environmental stimuli. Central to this regulation is chromatin remodeling, a dynamic and intricate process that alters the structure of chromatin—composed of DNA and histone proteins—thereby influencing the accessibility of transcriptional machinery to specific genomic regions. This accessibility is crucial for the activation or repression of genes in response to various cellular signals. Chromatin remodeling complexes, such as SWI/SNF, ISWI, and CHD, utilize energy derived from ATP hydrolysis to reposition, eject, or restructure nucleosomes, which significantly alters the chromatin landscape and consequently gene expression [1][2].

The significance of chromatin remodeling extends beyond basic biological processes; it plays a critical role in the pathogenesis of various diseases, particularly cancer. Dysregulation of chromatin remodeling complexes has been linked to aberrant gene expression patterns that drive tumorigenesis [3][4]. Understanding the mechanisms by which chromatin remodeling influences gene expression is therefore essential not only for elucidating fundamental biological processes but also for developing potential therapeutic strategies targeting these pathways. Recent studies have revealed complex interactions between chromatin remodelers and transcription factors, as well as the involvement of non-coding RNAs in modulating these processes [1][2].

Current research highlights the multifaceted nature of chromatin remodeling and its implications for health and disease. It is now recognized that chromatin structure is not merely a static entity but a dynamic one that can be influenced by various internal and external factors, including developmental cues and environmental stressors [5][6]. Moreover, advances in genomic technologies have provided deeper insights into the intricate regulatory networks that govern chromatin dynamics, revealing how these processes are integrated into broader cellular signaling pathways [7][8].

This review is organized as follows: we begin with an overview of chromatin structure, detailing the composition and organization of nucleosomes and higher-order chromatin structures. We then discuss the major chromatin remodeling complexes, including SWI/SNF, ISWI, and CHD, outlining their mechanisms of action and the role of ATP in facilitating chromatin remodeling. Subsequently, we explore how chromatin remodeling impacts gene expression, focusing on mechanisms of gene activation and repression, with case studies highlighting its significance in development and disease. The implications of chromatin remodeling in health and disease are examined, particularly its role in cancer and the potential for therapeutic targeting of chromatin remodelers. Finally, we conclude by summarizing the current understanding of chromatin dynamics in gene regulation and the future directions for research in this vital area of biomedical science.

By synthesizing recent findings and integrating various aspects of chromatin remodeling, this review aims to underscore the importance of chromatin dynamics in gene regulation and its potential as a therapeutic target in the context of disease [1][4].

2 Overview of Chromatin Structure ​

2.1 Nucleosome Composition and Organization ​

Chromatin remodeling is a fundamental process that plays a critical role in regulating gene expression by altering the structure and organization of chromatin, which is composed of DNA and histone proteins. This dynamic alteration of chromatin structure involves various enzymatic activities that catalyze covalent modifications of histone tails or facilitate the movement of nucleosomes along the DNA, thereby influencing gene accessibility and transcriptional activity.

Nucleosomes, the basic units of chromatin, consist of DNA wrapped around histone octamers. The composition and organization of nucleosomes are crucial for maintaining the structural integrity of chromatin and for regulating gene expression. Chromatin remodeling complexes, such as the SWI/SNF and INO80 complexes, utilize ATP hydrolysis to reposition nucleosomes, making certain genomic regions more or less accessible to transcription factors and other regulatory proteins. This repositioning can either facilitate or inhibit the transcription of specific genes, depending on the cellular context and the specific regulatory signals present.

Recent studies have shown that chromatin remodeling is tightly interconnected with other epigenetic mechanisms, including DNA methylation and non-coding RNA-mediated processes. For instance, histone modifications, such as acetylation and methylation, work in concert with chromatin remodeling to regulate gene expression epigenetically, without altering the underlying DNA sequence (Bure and Nemtsova, 2023) [1]. Moreover, the dynamic changes in chromatin conformation can lead to the formation of distinct topological domains that dictate gene expression distribution, highlighting the importance of chromatin architecture in cellular differentiation and gene regulation (Golkaram et al., 2017) [7].

The role of chromatin remodeling in gene expression is further emphasized by its involvement in various biological processes, including neural stem cell differentiation and circadian rhythm regulation. In neural stem cells, chromatin remodeling complexes are essential for fate determination, with specific protein complexes, such as REST/NRSF, playing critical roles in this process (Juliandi et al., 2010) [2]. Similarly, chromatin remodeling has been shown to regulate clock-controlled genes, linking circadian rhythms to gene expression through histone modification dynamics (Sahar and Sassone-Corsi, 2012) [9].

In summary, chromatin remodeling is a sophisticated mechanism that modulates gene expression through the dynamic organization of nucleosomes and the interplay of various epigenetic modifications. This regulation is vital for maintaining cellular identity and function, and its disruption can lead to various pathological conditions, including cancer and neurodegenerative diseases (Kumar et al., 2016) [3]. Understanding the intricate relationships between chromatin structure, nucleosome composition, and gene regulation holds significant potential for therapeutic interventions in various diseases.

2.2 Higher-Order Chromatin Structures ​

Chromatin remodeling plays a crucial role in regulating gene expression through dynamic alterations in chromatin structure, which are essential for various biological processes. The chromatin is organized into higher-order structures that influence accessibility to DNA, thereby determining the transcriptional activity of genes.

At the fundamental level, chromatin remodeling involves the repositioning of nucleosomes and the modification of histones, which can be mediated by ATP-dependent chromatin remodeling complexes such as SWI/SNF, INO80, and ISWI. These complexes utilize ATP hydrolysis to alter nucleosome positioning, thereby changing the local chromatin landscape and influencing gene accessibility (Jiang et al. 2023) [5]. This remodeling can create open chromatin regions that are more accessible to transcription factors and RNA polymerase, facilitating gene activation.

Moreover, chromatin remodeling is intricately linked with various epigenetic modifications, including DNA methylation and histone modifications such as acetylation and methylation. These modifications can serve as signals that guide the recruitment of chromatin remodelers to specific genomic regions. For instance, histone acetylation is often associated with active transcription and is recognized by bromodomain-containing proteins, which can recruit additional transcriptional machinery (Mahmoud & Poizat 2013) [10].

The structural organization of chromatin also plays a significant role in gene expression regulation. Higher-order chromatin structures, such as topologically associating domains (TADs), compartmentalize the genome and influence gene interactions. The dynamic nature of these structures allows for regulatory elements, such as enhancers and promoters, to come into proximity, facilitating transcriptional activation. For example, chromatin looping mediated by proteins like CTCF can bring distant enhancers into contact with target promoters, enhancing gene expression (Chai et al. 2020) [8].

Furthermore, chromatin remodeling is critical during developmental processes and cellular differentiation. The ability of chromatin to adopt different conformations allows for the precise control of gene expression patterns required for cell identity. Studies have shown that chromatin architecture changes during stem cell differentiation, leading to the activation of lineage-specific genes while repressing others (Golkaram et al. 2017) [7].

In pathological conditions, dysregulation of chromatin remodeling can lead to aberrant gene expression profiles, contributing to diseases such as cancer and neurodegenerative disorders. For instance, mutations in chromatin remodelers can disrupt normal gene expression programs, leading to oncogenesis (Kumar et al. 2016) [3].

In summary, chromatin remodeling is a fundamental mechanism that regulates gene expression by altering chromatin structure, facilitating the interaction of transcriptional machinery with DNA, and maintaining the integrity of higher-order chromatin structures. The interplay between chromatin remodelers, histone modifications, and the three-dimensional organization of the genome underscores the complexity of gene regulation and its implications for both normal development and disease states.

3 Chromatin Remodeling Complexes ​

3.1 SWI/SNF Complex ​

Chromatin remodeling is a critical process that regulates gene expression by altering the accessibility of DNA to transcription factors and other regulatory proteins. The SWI/SNF (Switch/Sucrose Non-Fermentable) complex, a prominent ATP-dependent chromatin remodeling complex, plays a pivotal role in this regulation.

The SWI/SNF complex is characterized by its ability to utilize the energy derived from ATP hydrolysis to disrupt histone-DNA interactions, thereby repositioning, ejecting, or shifting nucleosomes. This action makes the underlying DNA more accessible to transcription factors, facilitating the initiation of transcription and the subsequent expression of genes. The SWI/SNF complex is essential for the maintenance of lineage-specific enhancers, which are critical regulatory elements that control gene expression in a cell-type-specific manner. Research has demonstrated that SWI/SNF preferentially binds to long non-coding RNAs (lncRNAs) that direct the complex to these enhancers, thus reinforcing the role of lncRNAs in mediating enhancer activity and gene expression [11].

Moreover, the SWI/SNF complex has been implicated in a variety of cellular processes, including gene expression, nuclear organization, and chromosomal stability. Its components have been shown to be associated with regulatory elements integral to transcription, such as enhancers and promoters, indicating a broad role in gene regulation [12]. Notably, the distribution and activity of SWI/SNF complexes at enhancers are crucial for controlling the expression of genes linked to developmental processes, thereby influencing cell fate decisions [13].

The dynamic nature of the SWI/SNF complex allows it to respond to cellular signals, enabling it to modulate chromatin structure in a context-dependent manner. For instance, different configurations of SWI/SNF subunits can be associated with either high or low levels of gene expression, highlighting the complexity of its regulatory mechanisms [12]. This versatility is critical in developmental biology and has implications in disease states, particularly in cancer, where mutations in SWI/SNF components are frequently observed [14].

In summary, the SWI/SNF chromatin remodeling complex is a fundamental regulator of gene expression, facilitating the accessibility of DNA through its ATP-dependent remodeling activities. By interacting with lncRNAs and targeting specific enhancers, SWI/SNF orchestrates the precise regulation of gene expression essential for various cellular functions and developmental processes.

3.2 ISWI Complex ​

Chromatin remodeling is a crucial mechanism that regulates gene expression by altering the structure and accessibility of chromatin, thereby influencing the transcriptional activity of genes. The Imitation SWI (ISWI) chromatin remodeling complex plays a significant role in this process. ISWI is a member of the SWI2/SNF2 family of ATP-dependent chromatin remodelers, which are essential for various nuclear processes, including transcription regulation, DNA replication, and repair.

ISWI complexes operate primarily through ATP-dependent nucleosome sliding, which adjusts nucleosome positioning along the DNA. This repositioning can expose or obscure transcription factor binding sites, thus directly impacting gene expression. For instance, ISWI's activity in spacing nucleosomes is particularly vital at gene promoters, where it facilitates the accessibility of the transcriptional machinery. In Drosophila, studies have shown that loss of ISWI leads to significant transcriptional defects and alterations in higher-order chromatin structure, especially on the male X chromosome. Genome-wide surveys have revealed that ISWI binds to both genic and intergenic regions, influencing nucleosome positioning at transcription start sites, which is critical for proper transcriptional regulation (Sala et al., 2011) [15].

The regulation of gene expression by ISWI is also mediated through its interaction with long non-coding RNAs (lncRNAs). These lncRNAs can modulate the activity of chromatin remodelers, including ISWI, by affecting the assembly of specific complexes that promote either a differentiated or stem cell-like phenotype. For example, the interaction of lncBRM with the BRM subunit of the SWI/SNF complex inhibits its activity, thereby favoring the formation of a stem cell-related complex (Neve et al., 2021) [16].

Furthermore, ISWI's role extends to the regulation of higher-order chromatin structure. It has been shown that ISWI contributes to the compaction of chromatin by promoting the association of linker histone H1 with chromatin, which is crucial for maintaining chromatin integrity and proper gene expression (Corona et al., 2007) [17]. The loss of ISWI function can lead to decondensation of chromosomes and disruption of gene expression patterns, underscoring its importance in maintaining chromatin architecture (Bhat et al., 2025) [18].

In addition to its structural roles, ISWI complexes are implicated in the DNA damage response (DDR), which is essential for maintaining genomic integrity. They are involved in multiple DNA repair pathways, including homologous recombination and non-homologous end joining, further linking chromatin remodeling to gene expression regulation under stress conditions (Aydin et al., 2014) [19].

Overall, ISWI chromatin remodeling complexes regulate gene expression through a multifaceted approach that includes nucleosome repositioning, interaction with regulatory non-coding RNAs, maintenance of higher-order chromatin structure, and involvement in DNA repair processes. This complex interplay ensures that the transcriptional landscape is dynamically adjusted in response to developmental cues and environmental stimuli, highlighting the critical role of chromatin remodeling in cellular function and gene regulation.

3.3 CHD Complex ​

Chromatin remodeling is a crucial process that regulates gene expression by altering the structure and accessibility of chromatin, which in turn influences transcriptional activity. Chromatin remodeling complexes, including those from the CHD (chromodomain helicase DNA-binding) family, play significant roles in this regulatory mechanism.

Chromatin remodeling complexes are categorized into several families, with the CHD family being notable for its involvement in various cellular processes. These complexes can reposition nucleosomes, modify histones, and affect the overall chromatin architecture, thereby regulating gene transcription, DNA replication, and DNA repair. For instance, CHD4, a key component of the NuRD (nucleosome remodeling and deacetylase) complex, functions by repressing gene transcription through chromatin remodeling and histone deacetylation activities[20].

Research has shown that the CHD family, particularly CHD5 and CHD7, is involved in developmental processes and disease states. CHD5, for example, has been linked to the development of the nervous system and the pathogenesis of neuroblastomas, with its expression often reduced in cancerous tissues due to promoter hypermethylation[[pmid:12592387],[pmid:18698156]]. This reduction in expression can lead to altered chromatin structure and gene expression profiles associated with tumor development.

Moreover, CHD7 has been identified as a master regulator of neurogenesis, influencing the differentiation of neural stem cells by maintaining an open chromatin state at specific gene loci, such as the reelin (Reln) gene, which is crucial for cerebellar development[[pmid:28165338],[pmid:34588434]]. The loss of CHD7 function can result in significant developmental deficits, illustrating the importance of chromatin remodeling in regulating gene expression during neural development.

In addition to developmental roles, chromatin remodeling complexes also interact with non-coding RNAs (ncRNAs), which can further modulate gene expression. The interplay between ncRNAs and chromatin remodelers forms a complex regulatory network that influences cellular processes and responses to environmental cues[1].

Overall, chromatin remodeling complexes, particularly those within the CHD family, serve as vital regulators of gene expression by dynamically altering chromatin structure, thereby facilitating or inhibiting access to DNA for transcriptional machinery. This regulation is essential not only for normal development and cellular function but also in the context of various diseases, including cancers and neurodevelopmental disorders.

4 Mechanisms of Chromatin Remodeling ​

4.1 ATP-Dependent Remodeling ​

Chromatin remodeling plays a pivotal role in the regulation of gene expression, primarily through ATP-dependent mechanisms that alter chromatin structure, thereby influencing accessibility for transcription factors and other regulatory proteins. ATP-dependent chromatin remodeling complexes utilize the energy derived from ATP hydrolysis to reorganize chromatin, facilitating the transcription process.

The process of chromatin remodeling is essential for proper gene expression during various biological events, including development and differentiation. ATP-dependent chromatin remodeling complexes, such as SWI/SNF, INO80, ISWI, and CHD, are crucial for modifying the chromatin configuration. These complexes can induce localized changes in the DNA topology, which results in the formation of multiple remodeled nucleosomal states, thereby enhancing or repressing gene expression depending on the cellular context (Peterson 2002; Hota & Bruneau 2016).

One key mechanism by which these complexes function is through the alteration of nucleosome positioning. ATP-dependent chromatin remodeling activities can reposition nucleosomes along the DNA, thereby either exposing or occluding regulatory elements necessary for transcription factor binding. This repositioning is critical for ensuring that genes are appropriately activated or silenced in response to developmental cues or environmental stimuli (Whitehouse et al. 2000; Flaus & Owen-Hughes 2004).

Additionally, ATP-dependent chromatin remodeling is not solely limited to transcriptional activation. These complexes can also act as repressors of transcription. For instance, they can create a more compact chromatin structure that hinders the binding of transcription factors, thereby silencing gene expression. This dual functionality underscores the complexity of chromatin remodeling in gene regulation (Havas et al. 2001).

Moreover, recent studies have indicated that ATP-dependent chromatin remodeling interacts with other epigenetic mechanisms, such as histone modifications, to facilitate large-scale changes in chromatin structure necessary for gene expression during processes like memory formation and neurogenesis. These interactions are crucial for the activity-dependent regulation of gene expression, which is essential for both developing and adult brains (López et al. 2020; Jiang et al. 2023).

In summary, ATP-dependent chromatin remodeling is a dynamic process that regulates gene expression by modifying chromatin structure through nucleosome repositioning and altering the accessibility of DNA to transcriptional machinery. This regulation is critical for a wide range of cellular processes, including differentiation, development, and response to environmental changes.

4.2 Histone Modifications and Their Impact ​

Chromatin remodeling plays a crucial role in regulating gene expression through various mechanisms, primarily involving histone modifications. These modifications, which include acetylation, methylation, phosphorylation, and ubiquitination of histone proteins, serve as epigenetic markers that influence chromatin structure and function. The dynamic alteration of chromatin structure, facilitated by enzymatic activities, is essential for controlling access to DNA and, consequently, gene transcription.

Histone modifications are pivotal in the regulation of gene expression. They can lead to either an open chromatin configuration, which is conducive to transcription, or a closed configuration that represses gene activity. For instance, acetylation of histones generally correlates with active transcription by neutralizing the positive charge of histones, thereby reducing their affinity for negatively charged DNA and promoting a more relaxed chromatin structure. Conversely, methylation can either activate or repress transcription depending on the specific context and the amino acid residue being modified (Taniura et al., 2007) [21].

Recent studies have highlighted the role of ATP-dependent chromatin remodeling complexes, which work in conjunction with histone-modifying enzymes to facilitate large-scale changes in chromatin structure. These complexes utilize the energy derived from ATP hydrolysis to reposition nucleosomes, thereby altering the accessibility of DNA to transcription factors and other regulatory proteins essential for gene expression. This interplay between histone modifications and chromatin remodeling is critical for processes such as long-term memory formation and neural plasticity, indicating that chromatin structure is not static but rather a dynamic participant in gene regulation (López et al., 2020) [22].

Moreover, chromatin remodeling is influenced by external signals, such as circadian rhythms, which regulate gene expression through specific histone modifications. For example, CLOCK:BMAL1-mediated activation of clock-controlled genes is associated with rhythmic changes in histone modifications at their promoters, underscoring the connection between environmental cues and epigenetic regulation (Sahar & Sassone-Corsi, 2012) [9].

The stochastic nature of histone modification dynamics also contributes to the regulation of gene expression. Mathematical models suggest that the diffusion and recruitment properties of histone-modifying enzymes enable the formation of stable histone modification patterns that can influence gene activity. These patterns can establish or remove transcriptional states within minutes, highlighting the rapid responsiveness of chromatin to cellular signals (Anink-Groenen et al., 2014) [23].

In summary, chromatin remodeling regulates gene expression through a complex interplay of histone modifications and ATP-dependent mechanisms. These processes allow for the precise control of chromatin structure, enabling or inhibiting access to DNA for transcriptional machinery, and thus playing a fundamental role in various biological processes, including differentiation, memory formation, and responses to environmental stimuli.

4.3 Interactions with Transcription Factors ​

Chromatin remodeling is a critical process that regulates gene expression by altering the structure and accessibility of chromatin, thereby influencing the interactions between DNA and transcription factors. This process involves various mechanisms that can modulate the chromatin landscape, which in turn affects the transcriptional activity of genes.

One primary mechanism of chromatin remodeling is the action of ATP-dependent chromatin remodeling complexes. These complexes can disrupt histone-DNA interactions, facilitating the 'loosening' of chromatin at gene promoters, which is essential for the binding of transcription factors (Osley and Shen, 2006). This dynamic alteration of chromatin structure allows transcription factors to access their target sites on DNA, thereby promoting or repressing gene expression.

Furthermore, chromatin remodeling can occur through changes in histone composition and post-translational modifications of histones. These modifications can lead to alterations in higher-order chromatin structure, affecting the accessibility of genes for transcription. For instance, histone acetylation generally correlates with active transcription, as it reduces the positive charge on histones, decreasing their affinity for negatively charged DNA and thereby facilitating a more open chromatin conformation (Fisher and Franklin, 2011).

The interplay between chromatin remodeling and transcription factors is further exemplified by the observation that specific transcription factors can recruit chromatin remodelers to target genes. This recruitment can initiate local chromatin remodeling, which enhances the binding of additional transcription factors and the transcriptional machinery (Varga-Weisz and Becker, 1995). Moreover, recent studies have indicated that chromatin remodelers can also influence the transcription of metabolic genes, suggesting that they play a role in the broader regulatory networks that govern cellular responses to metabolic cues (Church et al., 2023).

Additionally, the three-dimensional organization of chromatin within the nucleus can impact gene expression by facilitating interactions between enhancers and promoters. Changes in chromatin conformation can bring distant regulatory elements into proximity, thereby enhancing transcriptional activation (Nuñez-Olvera et al., 2021). For example, the binding of oncogenic transcription factors has been shown to induce global changes in chromatin organization, which can lead to dysregulation of gene expression in cancer contexts (Elemento et al., 2012).

In summary, chromatin remodeling is a multifaceted process that regulates gene expression through the dynamic alteration of chromatin structure. It involves the actions of chromatin remodeling complexes, histone modifications, and the spatial organization of chromatin, all of which interact with transcription factors to modulate gene accessibility and transcriptional activity. These mechanisms underscore the importance of chromatin remodeling in maintaining cellular function and responding to environmental signals.

5 Role of Chromatin Remodeling in Gene Expression ​

5.1 Activation of Gene Transcription ​

Chromatin remodeling plays a crucial role in regulating gene expression by altering the structure and accessibility of chromatin, which directly influences the transcriptional activity of genes. This dynamic process is essential for various biological functions, including development, differentiation, and responses to environmental signals.

Chromatin remodeling involves enzymatic activities that catalyze covalent modifications of histone tails or reposition nucleosomes along the DNA. These modifications can either promote or inhibit access to transcription factors and the transcriptional machinery. For instance, the action of ATP-dependent chromatin remodeling complexes, such as the switch/sucrose nonfermentable (SWI/SNF) complex, is vital for controlling gene transcription by utilizing the energy from ATP hydrolysis to reposition nucleosomes, thereby facilitating or obstructing the binding of transcription factors to their target genes [24].

The recruitment of chromatin remodeling enzymes to promoter regions is a critical step in the activation of gene transcription. Recent studies suggest that gene-specific transcriptional activators target these enzymes sequentially, first directing an ATP-dependent SWI/SNF-like complex and then a histone acetyltransferase to the promoter region. This coordinated action establishes a chromatin structure that is permissive for transcription [25].

Moreover, the interplay between chromatin remodeling and histone modifications, such as acetylation and methylation, serves as a key regulatory mechanism. For example, histone acetylation generally correlates with active transcription, while methylation can have either activating or repressing effects depending on the specific context [2]. The modification of histones and the remodeling of chromatin can significantly impact gene accessibility, which is crucial for the transcriptional regulation of genes involved in various cellular processes.

In the context of stem cell differentiation, chromatin remodeling has been shown to dictate gene expression heterogeneity. The three-dimensional conformation of chromatin can fold into distinct topological domains, influencing transcriptional bursting and ultimately leading to a heterogeneous population of differentiated cells [7]. This highlights the importance of chromatin architecture in determining cell fate decisions.

Furthermore, the regulation of chromatin structure is also essential in the context of disease. Aberrant chromatin remodeling and the dysregulation of chromatin remodeling complexes have been linked to various pathologies, including cancer [26]. The understanding of how chromatin remodeling interacts with non-coding RNAs (ncRNAs) and other epigenetic factors can provide insights into the regulatory networks that govern gene expression in both normal and pathological conditions [1].

In summary, chromatin remodeling is a fundamental mechanism that regulates gene expression through the dynamic alteration of chromatin structure. By controlling the accessibility of DNA to transcription factors and modifying histone proteins, chromatin remodeling complexes orchestrate the intricate balance of gene activation and repression, which is vital for cellular function and development.

5.2 Gene Repression Mechanisms ​

Chromatin remodeling plays a crucial role in the regulation of gene expression through various mechanisms that facilitate or inhibit the accessibility of DNA to transcriptional machinery. This dynamic alteration of chromatin structure is essential for numerous biological processes, including development, differentiation, and responses to environmental signals.

At the molecular level, chromatin remodeling is achieved through the action of ATP-dependent chromatin remodeling complexes, which utilize energy from ATP hydrolysis to reposition nucleosomes, thereby altering the chromatin landscape. These complexes can modify histone tails through covalent modifications such as acetylation, methylation, phosphorylation, and ubiquitination, which further influence chromatin accessibility and gene transcription. For instance, histone acetylation is generally associated with gene activation, while histone methylation can either activate or repress gene expression depending on the specific context and location of the modifications [2][27].

One of the key aspects of chromatin remodeling is its role in gene repression mechanisms. Chromatin remodeling complexes can lead to the formation of a more compact chromatin structure, which physically obstructs the binding of transcription factors and RNA polymerase to the DNA. For example, the RE1 silencer of transcription/neuron-restrictive silencer factor (REST/NRSF) complex is known to recruit chromatin remodeling activities that repress neuronal gene expression in non-neuronal cells, thereby maintaining cell identity and function [2].

Additionally, the interaction between chromatin remodelers and non-coding RNAs (ncRNAs) has been identified as a significant regulatory mechanism. ncRNAs can guide chromatin remodeling complexes to specific genomic regions, influencing the local chromatin structure and, consequently, gene expression patterns. This mutual regulation between ncRNAs and chromatin remodeling complexes forms a complex network that can fine-tune gene expression in response to cellular conditions [1].

Moreover, the intricate regulation of chromatin dynamics is critical in the context of pathological conditions, such as cancer. Dysregulation of chromatin remodeling factors can lead to aberrant gene expression profiles that contribute to oncogenesis. Alterations in the activity or expression of chromatin remodelers can disrupt the balance between gene activation and repression, resulting in the inappropriate expression of oncogenes or tumor suppressor genes [3].

In summary, chromatin remodeling is a vital process that regulates gene expression through the repositioning of nucleosomes, modification of histones, and interaction with non-coding RNAs. These mechanisms are essential for maintaining cellular identity and responding to environmental changes, and their dysregulation can have significant implications for various diseases, including cancer and neurodegenerative disorders. Understanding the precise roles of chromatin remodeling in gene repression mechanisms can provide insights into therapeutic strategies aimed at modulating gene expression for disease treatment [5][28].

5.3 Case Studies: Development and Disease ​

Chromatin remodeling plays a crucial role in regulating gene expression by altering the structure of chromatin, thereby influencing the accessibility of DNA to transcription factors and other regulatory proteins. This process is essential for various biological phenomena, including development and disease.

In the context of development, chromatin remodeling is involved in determining gene expression heterogeneity during stem cell differentiation. Golkaram et al. (2017) incorporated three-dimensional chromosomal conformation data and single-cell RNA sequencing to show that chromatin reorganization can dictate gene expression distribution. Their findings suggest that local DNA density during differentiation enhances transcriptional bursting due to the crowding effect of chromatin, resulting in a heterogeneous cell population that increases the differentiation potential of stem cells[7].

Furthermore, chromatin remodeling is integral to the regulation of oncogenesis. Kumar et al. (2016) emphasized that disruptions in gene expression programs, often associated with acquired therapeutic resistance, can lead to cancer progression. They noted that chromatin remodelers integrate extracellular and cytoplasmic signals to control gene activity. The dysregulation of these remodelers, which affects the expression of critical regulatory genes, is a significant mechanism driving tumor growth and progression[3].

In the context of stem cell differentiation, chromatin remodeling complexes interact with various epigenetic mechanisms, including histone modifications and DNA methylation. Juliandi et al. (2010) discussed how chromatin remodeling is influenced by enzymatic activities that modify histones or reposition nucleosomes along the DNA. This dynamic alteration of chromatin structure is crucial for regulating gene expression epigenetically, thus affecting cell fate decisions during neural stem cell differentiation[2].

The impact of chromatin remodeling is also evident in the study of human diseases. Liu et al. (2008) highlighted that aberrations in chromatin remodeling are associated with complex diseases such as cancer and type 2 diabetes. They emphasized that the regulation of gene expression through chromatin remodeling processes is vital for integrating environmental signals, which modulate the functional output of the genome[29].

In summary, chromatin remodeling is a fundamental process that regulates gene expression by modifying chromatin structure, thereby controlling the accessibility of DNA to transcriptional machinery. This regulation is crucial for normal development and is implicated in various diseases, particularly cancers, where dysregulation of chromatin remodeling can lead to altered gene expression patterns and therapeutic resistance. The studies cited illustrate the diverse mechanisms by which chromatin remodeling influences gene expression in both developmental contexts and disease states.

6 Implications in Health and Disease ​

6.1 Chromatin Remodeling in Cancer ​

Chromatin remodeling plays a crucial role in regulating gene expression by altering the structure of chromatin, thereby influencing the accessibility of DNA to transcriptional machinery. This process is essential for the proper expression of genes and is mediated by various chromatin remodeling complexes and associated proteins. The dysregulation of these mechanisms can lead to oncogenesis and other diseases.

Chromatin remodeling involves the repositioning or restructuring of nucleosomes, which can be accomplished through ATP-dependent chromatin remodeling complexes or by post-translational modifications of histones. These modifications include acetylation, methylation, phosphorylation, and ubiquitination, which can either promote or inhibit transcription depending on the specific context. For instance, the movement of nucleosomes can expose or hide regulatory regions of DNA, such as promoters and enhancers, from the transcriptional machinery, thus directly impacting gene expression levels [26].

In cancer, the disruption of chromatin remodeling is a significant factor contributing to the aberrant gene expression patterns observed in malignant cells. A substantial body of evidence indicates that mutations in chromatin remodeling genes, such as ARID1A, are frequently associated with various cancers, particularly those arising from the endometrial epithelium, such as ovarian clear cell carcinoma and uterine endometrioid carcinomas [30]. These mutations often lead to the dysregulation of gene expression programs that are critical for maintaining normal cellular functions, thus facilitating tumor development and progression [3].

Furthermore, chromatin remodeling complexes have been implicated in the development of therapeutic resistance in cancer. The dynamic nature of chromatin allows cancer cells to adapt to therapeutic pressures by altering gene expression patterns that promote survival and proliferation. For example, in prostate cancer, chromatin reprogramming has been observed as a response to targeted therapies, leading to increased DNA accessibility and altered gene expression that contributes to treatment resistance [31].

Recent studies have highlighted the potential of targeting chromatin remodeling factors as a therapeutic strategy. Selective inhibitors of chromatin remodelers and bromodomains have emerged as promising candidates for pharmacological intervention, either as monotherapies or in combination with existing chemotherapeutics and radiotherapy [3]. This approach aims to restore normal gene expression patterns and counteract the effects of dysregulated chromatin in cancer cells.

In summary, chromatin remodeling is a vital mechanism that regulates gene expression through structural alterations of chromatin, impacting various cellular processes. Its dysregulation is closely linked to the pathogenesis of cancer, highlighting the importance of understanding these processes for developing effective therapeutic strategies. The interplay between chromatin dynamics and gene expression not only underscores the complexity of cancer biology but also opens avenues for innovative treatment modalities targeting the epigenetic landscape of tumors [32][33].

6.2 Potential Therapeutic Targets ​

Chromatin remodeling is a critical process that influences gene expression by altering the structure of chromatin, thereby facilitating or hindering the accessibility of transcriptional machinery to specific genes. This process is primarily mediated by multi-protein complexes that perform enzymatic activities to modify histones and reposition nucleosomes along the DNA. Such modifications can include histone acetylation, methylation, and other post-translational modifications, which play essential roles in the epigenetic regulation of gene expression without altering the underlying DNA sequence.

The relationship between chromatin remodeling and gene expression is deeply intertwined with various biological processes, including cellular differentiation, proliferation, and responses to environmental stimuli. For instance, in neural stem cells, chromatin remodeling complexes are essential for determining cell fate by regulating gene expression in response to intrinsic and extrinsic signals. These regulatory complexes can either promote or inhibit the transcription of target genes, which is vital for maintaining the balance between self-renewal and differentiation of stem cells (Juliandi et al., 2010) [2].

In health, proper chromatin remodeling is crucial for normal cellular function. However, in disease states, particularly cancer, the dysregulation of chromatin remodeling complexes can lead to aberrant gene expression patterns that contribute to tumorigenesis. Disruption of the intricate gene expression program is a significant driving factor in cancer development, often linked to mutations and epigenetic alterations that affect chromatin structure and function. For example, chromatin remodelers have been implicated in therapeutic resistance, where cancer cells adapt to treatments by altering their chromatin landscape, thereby evading apoptosis or other therapeutic effects (Kumar et al., 2016) [3].

The therapeutic potential of targeting chromatin remodeling mechanisms is increasingly recognized. Interventions aimed at modifying chromatin structure or function have shown promise in various disease contexts, particularly in cardiovascular diseases and malignancies. For instance, advancements in understanding chromatin architecture have led to novel therapeutic strategies for heart failure, utilizing bioinformatics and gene therapy approaches to target specific cardiac genes and chromatin remodeler complexes (Kraus & Beavens, 2023) [34]. Furthermore, the development of drugs that target chromatin-modifying enzymes presents a potential avenue for treating cancers characterized by dysregulated chromatin dynamics (Keppler & Archer, 2008) [35].

In summary, chromatin remodeling plays a pivotal role in regulating gene expression through dynamic structural changes that influence transcriptional accessibility. The implications of these processes are profound in both health and disease, highlighting the potential for therapeutic targeting of chromatin remodeling complexes and associated pathways to treat various conditions, particularly cancers and cardiovascular diseases. Continued research into the mechanisms of chromatin remodeling will be essential for developing effective therapeutic strategies that leverage these insights.

7 Conclusion ​

This review highlights the critical role of chromatin remodeling in the regulation of gene expression, emphasizing its dynamic nature and implications for both normal biological processes and disease states. Key findings indicate that chromatin remodeling complexes, such as SWI/SNF, ISWI, and CHD, utilize ATP hydrolysis to reposition nucleosomes, thereby modulating DNA accessibility for transcription factors. The interplay between chromatin structure, histone modifications, and non-coding RNAs underscores the complexity of gene regulation. Current research reveals that dysregulation of chromatin remodeling is linked to various diseases, particularly cancer, where altered gene expression patterns drive tumorigenesis and therapeutic resistance. Future studies should focus on elucidating the intricate regulatory networks governing chromatin dynamics and exploring novel therapeutic strategies targeting these pathways to improve treatment outcomes in cancer and other diseases.

References ​

  • [1] Irina V Bure;Marina V Nemtsova. Mutual Regulation of ncRNAs and Chromatin Remodeling Complexes in Normal and Pathological Conditions.. International journal of molecular sciences(IF=4.9). 2023. PMID:37175555. DOI: 10.3390/ijms24097848.
  • [2] Berry Juliandi;Masahiko Abematsu;Kinichi Nakashima. Chromatin remodeling in neural stem cell differentiation.. Current opinion in neurobiology(IF=5.2). 2010. PMID:20434901. DOI: 10.1016/j.conb.2010.04.001.
  • [3] R Kumar;D-Q Li;S Müller;S Knapp. Epigenomic regulation of oncogenesis by chromatin remodeling.. Oncogene(IF=7.3). 2016. PMID:26804164. DOI: 10.1038/onc.2015.513.
  • [4] Cedric R Clapier. Sophisticated Conversations between Chromatin and Chromatin Remodelers, and Dissonances in Cancer.. International journal of molecular sciences(IF=4.9). 2021. PMID:34070411. DOI: 10.3390/ijms22115578.
  • [5] Dongfang Jiang;Tingting Li;Caixia Guo;Tie-Shan Tang;Hongmei Liu. Small molecule modulators of chromatin remodeling: from neurodevelopment to neurodegeneration.. Cell & bioscience(IF=6.2). 2023. PMID:36647159. DOI: 10.1186/s13578-023-00953-4.
  • [6] Juline Auverlot;Avilien Dard;Julio Sáez-Vásquez;Jean-Philippe Reichheld. Redox regulation of epigenetic and epitranscriptomic gene regulatory pathways in plants.. Journal of experimental botany(IF=5.7). 2024. PMID:38642408. DOI: 10.1093/jxb/erae165.
  • [7] Mahdi Golkaram;Jiwon Jang;Stefan Hellander;Kenneth S Kosik;Linda R Petzold. The Role of Chromatin Density in Cell Population Heterogeneity during Stem Cell Differentiation.. Scientific reports(IF=3.9). 2017. PMID:29042584. DOI: 10.1038/s41598-017-13731-3.
  • [8] Peiwei Chai;Jie Yu;Ruobing Jia;Xuyang Wen;Tianyi Ding;Xiaoyu Zhang;Hongyan Ni;Renbing Jia;Shengfang Ge;He Zhang;Xianqun Fan. Generation of onco-enhancer enhances chromosomal remodeling and accelerates tumorigenesis.. Nucleic acids research(IF=13.1). 2020. PMID:33196849. DOI: 10.1093/nar/gkaa1051.
  • [9] Saurabh Sahar;Paolo Sassone-Corsi. Circadian rhythms and memory formation: regulation by chromatin remodeling.. Frontiers in molecular neuroscience(IF=3.8). 2012. PMID:22470318. DOI: 10.3389/fnmol.2012.00037.
  • [10] Salma Awad Mahmoud;Coralie Poizat. Epigenetics and chromatin remodeling in adult cardiomyopathy.. The Journal of pathology(IF=5.2). 2013. PMID:23813473. DOI: 10.1002/path.4234.
  • [11] James A Oo;Timothy Warwick;Katalin Pálfi;Frederike Lam;Francois McNicoll;Cristian Prieto-Garcia;Stefan Günther;Can Cao;Yinuo Zhou;Alexey A Gavrilov;Sergey V Razin;Alfredo Cabrera-Orefice;Ilka Wittig;Soni Savai Pullamsetti;Leo Kurian;Ralf Gilsbach;Marcel H Schulz;Ivan Dikic;Michaela Müller-McNicoll;Ralf P Brandes;Matthias S Leisegang. Long non-coding RNAs direct the SWI/SNF complex to cell type-specific enhancers.. Nature communications(IF=15.7). 2025. PMID:39747144. DOI: 10.1038/s41467-024-55539-6.
  • [12] Ghia M Euskirchen;Raymond K Auerbach;Eugene Davidov;Tara A Gianoulis;Guoneng Zhong;Joel Rozowsky;Nitin Bhardwaj;Mark B Gerstein;Michael Snyder. Diverse roles and interactions of the SWI/SNF chromatin remodeling complex revealed using global approaches.. PLoS genetics(IF=3.7). 2011. PMID:21408204. DOI: 10.1371/journal.pgen.1002008.
  • [13] Burak H Alver;Kimberly H Kim;Ping Lu;Xiaofeng Wang;Haley E Manchester;Weishan Wang;Jeffrey R Haswell;Peter J Park;Charles W M Roberts. The SWI/SNF chromatin remodelling complex is required for maintenance of lineage specific enhancers.. Nature communications(IF=15.7). 2017. PMID:28262751. DOI: 10.1038/ncomms14648.
  • [14] Ziwei Li;Jiumei Zhao;Yu Tang. Advances in the role of SWI/SNF complexes in tumours.. Journal of cellular and molecular medicine(IF=4.2). 2023. PMID:36883311. DOI: 10.1111/jcmm.17709.
  • [15] Anna Sala;Maria Toto;Luca Pinello;Alessandra Gabriele;Valeria Di Benedetto;Antonia M R Ingrassia;Giosuè Lo Bosco;Vito Di Gesù;Raffaele Giancarlo;Davide F V Corona. Genome-wide characterization of chromatin binding and nucleosome spacing activity of the nucleosome remodelling ATPase ISWI.. The EMBO journal(IF=8.3). 2011. PMID:21448136. DOI: 10.1038/emboj.2011.98.
  • [16] Bernadette Neve;Nicolas Jonckheere;Audrey Vincent;Isabelle Van Seuningen. Long non-coding RNAs: the tentacles of chromatin remodeler complexes.. Cellular and molecular life sciences : CMLS(IF=6.2). 2021. PMID:33001247. DOI: 10.1007/s00018-020-03646-0.
  • [17] Davide F V Corona;Giorgia Siriaco;Jennifer A Armstrong;Natalia Snarskaya;Stephanie A McClymont;Matthew P Scott;John W Tamkun. ISWI regulates higher-order chromatin structure and histone H1 assembly in vivo.. PLoS biology(IF=7.2). 2007. PMID:17760505. DOI: 10.1371/journal.pbio.0050232.
  • [18] Younus A Bhat;Javaid Y Bhat;Suhail A Shiek;Mohmmad Abaas Dar;Shajrul Amin;Craig L Peterson;Jayant B Udgaonkar;Ajazul H Wani. Dynamic Conformations of Chromatin Remodeler ISWI during Nucleosome Sliding Revealed by Hydrogen-Deuterium Exchange Coupled to Mass Spectrometry.. Biochemistry(IF=3.0). 2025. PMID:40982624. DOI: 10.1021/acs.biochem.5c00330.
  • [19] Özge Z Aydin;Wim Vermeulen;Hannes Lans. ISWI chromatin remodeling complexes in the DNA damage response.. Cell cycle (Georgetown, Tex.)(IF=3.4). 2014. PMID:25486562. DOI: 10.4161/15384101.2014.956551.
  • [20] Wei Shi;Lauren K Wasson;Kerry M Dorr;Zachary L Robbe;Caralynn M Wilczewski;Austin J Hepperla;Ian J Davis;Christine E Seidman;Jonathan G Seidman;Frank L Conlon. CHD4 and SMYD1 repress common transcriptional programs in the developing heart.. Development (Cambridge, England)(IF=3.6). 2024. PMID:38619323. DOI: 10.1242/dev.202505.
  • [21] Hideo Taniura;Judy C G Sng;Yukio Yoneda. Histone modifications in the brain.. Neurochemistry international(IF=4.0). 2007. PMID:17543419. DOI: 10.1016/j.neuint.2007.04.018.
  • [22] Alberto J López;Julia K Hecking;André O White. The Emerging Role of ATP-Dependent Chromatin Remodeling in Memory and Substance Use Disorders.. International journal of molecular sciences(IF=4.9). 2020. PMID:32957495. DOI: 10.3390/ijms21186816.
  • [23] Lisette C M Anink-Groenen;Timo R Maarleveld;Pernette J Verschure;Frank J Bruggeman. Mechanistic stochastic model of histone modification pattern formation.. Epigenetics & chromatin(IF=3.5). 2014. PMID:25408711. DOI: 10.1186/1756-8935-7-30.
  • [24] Yanyan Tang;Jinpeng Wang;Yu Lian;Chunmei Fan;Ping Zhang;Yingfen Wu;Xiayu Li;Fang Xiong;Xiaoling Li;Guiyuan Li;Wei Xiong;Zhaoyang Zeng. Linking long non-coding RNAs and SWI/SNF complexes to chromatin remodeling in cancer.. Molecular cancer(IF=33.9). 2017. PMID:28212646. DOI: 10.1186/s12943-017-0612-0.
  • [25] C J Fry;C L Peterson. Chromatin remodeling enzymes: who's on first?. Current biology : CB(IF=7.5). 2001. PMID:11267889. DOI: 10.1016/s0960-9822(01)00090-2.
  • [26] Penny K Davis;Rainer K Brackmann. Chromatin remodeling and cancer.. Cancer biology & therapy(IF=4.6). 2003. PMID:12673113. DOI: 10.4161/cbt.189.
  • [27] Hui He;Zhiping Hu;Han Xiao;Fangfang Zhou;Binbin Yang. The tale of histone modifications and its role in multiple sclerosis.. Human genomics(IF=4.3). 2018. PMID:29933755. DOI: 10.1186/s40246-018-0163-5.
  • [28] Pei Han;Calvin T Hang;Jin Yang;Ching-Pin Chang. Chromatin remodeling in cardiovascular development and physiology.. Circulation research(IF=16.2). 2011. PMID:21293009. DOI: 10.1161/CIRCRESAHA.110.224287.
  • [29] Liang Liu;Yuanyuan Li;Trygve O Tollefsbol. Gene-environment interactions and epigenetic basis of human diseases.. Current issues in molecular biology(IF=3.0). 2008. PMID:18525104. DOI: .
  • [30] Tsui-Lien Mao;Ie-Ming Shih. The roles of ARID1A in gynecologic cancer.. Journal of gynecologic oncology(IF=3.7). 2013. PMID:24167674. DOI: 10.3802/jgo.2013.24.4.376.
  • [31] Peder Rustøen Braadland;Alfonso Urbanucci. Chromatin reprogramming as an adaptation mechanism in advanced prostate cancer.. Endocrine-related cancer(IF=4.6). 2019. PMID:30844748. DOI: .
  • [32] Xiaoman Zhang;Dequan Liu;Xiaochi Chen;Tian Li;Guangzhen Wu. Chromatin and epigenetic regulation in malignant tumors: A comprehensive review.. Annals of the New York Academy of Sciences(IF=4.8). 2025. PMID:40760787. DOI: 10.1111/nyas.70005.
  • [33] Francesca Citron;Linda Fabris. Targeting Epigenetic Dependencies in Solid Tumors: Evolutionary Landscape Beyond Germ Layers Origin.. Cancers(IF=4.4). 2020. PMID:32183227. DOI: 10.3390/cancers12030682.
  • [34] Lindsay Kraus;Brianna Beavens. The Current Therapeutic Role of Chromatin Remodeling for the Prognosis and Treatment of Heart Failure.. Biomedicines(IF=3.9). 2023. PMID:36831115. DOI: 10.3390/biomedicines11020579.
  • [35] Brian R Keppler;Trevor K Archer. Chromatin-modifying enzymes as therapeutic targets--Part 1.. Expert opinion on therapeutic targets(IF=4.4). 2008. PMID:18781828. DOI: 10.1517/14728222.12.10.1301.

MaltSci Intelligent Research Services ​

Search for more papers on MaltSci.com ​

Chromatin Remodeling · Gene Expression · Tumorigenesis

© 2025 MaltSci