Epigenetic roles of chromatin remodeling complexes in bone biology and the pathogenesis of bone‑related disease (Review)

Abstract

Chromatin remodeling complexes are essential regulators of chromatin architecture, facilitating critical processes such as nucleosome sliding, eviction, histone exchange and post‑translational modifications. By providing an additional layer of epigenetic regulation beyond the canonical genetic code, these complexes significantly influence bone biology and health. Epigenetic regulation through chromatin remodeling complexes is crucial in modulating gene expression and cellular behavior in bone cells. However, alterations in the activity of chromatin remodeling complexes can also contribute to the progression of various bone diseases. Emerging evidence suggests that specific chromatin remodeling factors may serve as potential biomarkers for diagnosing bone‑related conditions and as therapeutic targets for intervention. The present review aims to elucidate the intricate relationship between chromatin remodeling complexes and bone‑related diseases, including osteoporosis, osteoarthritis and osteosarcoma. The present review discusses the diverse subunits of these complexes and their multifaceted roles in regulating key cellular processes such as stemness, differentiation, proliferation, senescence and apoptosis in bone cells. Notably, the present review provides a comprehensive overview of the roles of various chromatin remodeling subunits, such as BRG1, BAF47 and chromodomain‑helicase‑DNA binding 7 (CHD7), in bone metabolism, highlighting their disease‑specific mechanisms, including bromodomain‑containing protein (BRD)9‑mediated pyroptosis in intervertebral disc degeneration and CHD7‑driven bone‑fat imbalance. Furthermore, the present review highlights the therapeutic potential of targeting dysfunctional subunits (such as BRD7 in osteosarcoma and SS18 in synovial sarcoma) and propose AI‑driven structural biology approaches to design chemical modulators. The understudied impact of aging on chromatin remodeling activity in bone homeostasis is also underscored, advocating for longitudinal studies to address this gap. Finally, the distinct functions of each chromatin remodeling complex and its specific subunits in the context of bone‑related diseases were also explored, providing a comprehensive understanding of their contributions to both normal bone physiology and pathological conditions.

Keywords: bone biology; bone development; bone‑related diseases; chromatin remodeling complexes; epigenetic regulation.

Figure 1

During gene transcription, chromatin remodeling complexes restructure the chromatin and nucleosomes in mainly three aspects: Chromatin access, nucleosome assembly and nucleosome editing. TF, transcription factor; SWI/SNF, switch/sucrose non-fermentable complex; CHD, chromodomain-helicase-DNA binding protein; INO80, inositol requiring 80 complex; ISWI, imitation switch complex. This figure was created with BioRender.com.

Figure 2

Chromatin remodeling complexes have diverse subtypes to implement their indispensable functions. Chromatin remodeling complexes are categorized into four distinct families: SWI/SNF, ISWI, CHD and INO80/SWR. The SWI/SNF family complexes in human cells are characterized by a marked diversity of assemblies. There are several variants of this complex, including the cBAF, PBAF and ncBAF/gBAF subtypes, which are large assemblies with core subunits such as BRG1/BRM (ATPase), BAF155/BAF170 (scaffold proteins), BAF47 (tumor suppressor) and BAF60 (linking proteins to transcription factors). The ISWI family complexes, including NURF, CHRAC and ACF, feature key subunits such as the ATPase ISWI (SMARCA1/SMARCA5), the large chromatin-binding NURF301 (BPTF), the accessory proteins CHRAC15/CHRAC17 and the scaffold protein ACF1 (BAZ1A). The CHD family complexes, ranging from CHD1 to CHD9, include subunits such as CHD1/CHD2 (chromodomains for histone binding) and CHD3/CHD4 (NuRD complex) with ATPase activity. In INO80/SWR family complexes, INO80 and SWR are presented separately since, although they belong to the same family of chromatin remodelers, they are classified into different subfamilies with distinct components. Crucial for histone exchange, these complexes include subunits such as the INO80 ATPase, RVB1/RVB2 for structural integrity and, within the SWR1 complex, the SWR1 ATPase, Swc2 for binding H2A.Z and Swc5/Swc6 for histone variant incorporation. cBAF, canonical BAF; ncBAF, non-canonical BAF; BCL7A-C, B-cell lymphoma 7A-C; BAF, brahma-associated factor; ACTB, β actin; SS18, synovial sarcoma translocation protein 18; ARID1A/B, AT-rich interactive domain 1A/B; BRD, bromodomain-containing protein; PBRM1, polybromo-1; PBAF, polybromo-associated BAF; GLTSCR1/GLTSCR1L, glioma tumor suppressor candidate region gene 1/glioma tumor suppressor candidate region gene 1-like; gBAF, germinal center B-cell-specific BAF; SWI/SNF, switching defective/sucrose non-fermenting; ACF-5, ATP-dependent chromatin assembly and remodeling factor-5; WICH, WSTF-ISWI chromatin-remodeling complex; NURF, nucleosome remodeling factor; NORC, nucleolar remodeling complex; RSF, remodeling and spacing factor; CERF-5, chromatin-associated Ets-related factor-5; ISWI, imitation SWI; ACE, activating chromatin element; CERF-1, chromatin-associated Ets-related factor-1; CHRAC-1, chromatin accessibility complex-1; CHD, Chromodomain-helicase-DNA-binding; ARP5. COM, actin-related protein 5 complex; ARP8 module, actin-related protein 8 module; NHP10 module, non-histone protein 10 module; INO80, inositol-requiring 80; SWR1, Swi2/Snf2-related 1; C-Module, C-terminal module; N-Module, N-terminal module. This figure was created with BioRender.com.

Figure 3

Chromatin remodeling complexes are under three main regulation factors: Non-coding RNA, actin and actin-related proteins, post-translational modifications. Non-coding RNA: i) miRNAs mediate translational repression or target mRNA degradation by assembling the RISC, thereby inhibiting the expression of subunits of the chromatin remodeling complex; ii) lncRNA inhibits the assembly of the chromatin remodeling complex by binding to its subunits; iii) lncRNA facilitates the recruitment of chromatin remodeling complexes to target gene promoter regions, thereby promoting gene expression; and iv) lncRNA represses gene expression by preventing the binding of chromatin remodeling complexes, thereby inhibiting chromatin remodeling. Actin and actin-related proteins: These proteins serve as components of chromatin remodeling complexes, influencing gene expression and DNA repair processes. They facilitate chromatin remodeling by directly binding to histones and promoting ATP hydrolysis through interaction with ATPase. Additionally, actin-related proteins bridge HAT and chromatin remodeling complexes, thereby positively coordinating their functions. Posttranslational modifications: Chromatin remodeling complexes are regulated by the histone post-translational modifications including phosphorylation, acetylation and PARylation. RISC, RNA-induced silencing complex; ORF, open reading frame; TSS, transcription start site; HAT, histone acetyltransferase; Ac, acetyl; MACROD1, macrodomain-containing protein 1; TARG1, tankyrase-associated RING-containing protein 1; PARG, poly (ADP-ribose) glycohydrolase; ARH3, ADP-ribosylhydrolase 3; PARP1, poly (ADP-ribose) polymerase 1. This figure was created with BioRender.com.

Figure 4

Epigenetic roles of chromatin remodeling complexes in bone metabolic processes, including stemness maintenance, chondrogenesis, osteogenesis and osteoclastgenesis. This figure shows how each relevant subunit, through its unique molecular mechanism, performs epigenetic changes including in normal and pathological conditions. AOC/C-E3 ligase, activator of c-Jun/C-E3 ligase; BAF, brahma-associated factor; BMP, bone morphogenetic protein; BRD, bromodomain-containing protein; BRG1, breast cancer susceptibility gene 1-associated protein; BRM, bromodomain-containing protein BRM; CHD, chromodomain-helicase-DNA-binding protein; EWS-FLI1, Ewing sarcoma breakpoint region 1-Friend leukemia virus integration 1 transcription factor; EWSR1, Ewing sarcoma breakpoint region 1; FGFR3, fibroblast growth factor receptor 3; Foxp1, forkhead Box Protein P1; INO80, inositol-requiring 80; IFN-B, interferon-β; MSC, mesenchymal stem cell; OCT4, octamer-binding transcription factor 4; Ptch1, Patched-1; Runx2, Runt-related transcription factor 2; Shh/Gli, Sonic hedgehog/glioma-associated oncogene family zinc-finger protein; Siglec15, sialic acid-binding immunoglobulin-like lectin 15; SMAD1-SP7, SMAD family protein 1-specificity protein 7; SOX2, Sex-determining region Y-box 2; SP1, specificity protein 1; SS18, synovial sarcoma translocation protein 18; SSLO-SSX, synovial sarcoma X-breakpoint gene; TSS, transcription start site. This figure was created with BioRender.com.

Figure 5

Chromatin remodeling complexes employ various biological regulatory mechanisms that contribute to the balance of bone development. This figure illustrates eight well-established mechanisms involved in chondrogenesis, osteogenesis, osteoclastogenesis and adipogenesis, each characterized by its unique features. Gli2/3, glioma-associated oncogene family zinc-finger protein 2/3; SWI/SNF, switch/sucrose non-fermentable; BAF, brahma-associated factor; Ptch1, Patched-1; Pol II, RNA polymerase II; RISC, RNA-induced silencing complex; ORF, open reading frame; TSS, transcription start site; HAT, histone acetyltransferase; Ac, acetyl group; MACROD, macrodomain-containing protein; TARG1, tumor necrosis factor α receptor-associated protein 1; PARG, Poly (ADP-ribose) glycohydrolase; ARH3, ADP-ribosylhydrolase 3; PARP1, Poly (ADP-ribose) polymerase 1; P38 MAPK, p38 mitogen-activated protein kinase; BRG1, brahma-related gene 1; Sp1, specificity protein 1; FGFR3, fibroblast growth factor receptor 3; RUNX2, Runt-related transcription factor 2; PBAF, polybromo-associated BAF; RXR, retinoid X receptor; VDR, vitamin D receptor; VDRE, vitamin D response element; Dlx5, Distal-less homeobox 5; BMP2, bone morphogenetic protein 2; Bglap, Bone γ-carboxyglutamate-containing protein; CHD7, chromodomain-helicase-DNA-binding protein 7; H3K4me3, Histone H3 lysine 4 trimethylation; PPAR-γ, peroxisome proliferator-activated receptor γ; Cebpa, CCAAT-enhancer-binding protein α; Adiopoq, adiponectin; Plin1, perilipin 1; CD36, NF-κB, nuclear factor-κB; RANKL, receptor activator of NF-κB ligand; M-CSF, macrophage colony-stimulating Factor; CBAF, chromatin assembly factor; BRD9, bromodomain-containing protein 9; FOXP1, forkhead box protein P1. This figure was created with BioRender.com.

Figure 6

Epigenetic roles of chromatin remodeling complexes in bone biological functions. There are three other bone-related processes in which chromatin remodeling complexes and their essential subunits are involved. This figure demonstrates how each relevant subunit utilizes its distinct molecular mechanism to achieve epigenetic modifications, both under normal and pathological conditions. BAF, BRG1-associated factor; Ric-8B, regulator of G-protein signaling 8B; BRG1, brahma-related gene 1; Bcl11b, B-cell lymphoma/leukemia 11B; MKI67, marker of proliferation Ki-67; BAZ1A, bromodomain-adjacent to Zinc finger domain 1A; NoRC, nucleolar remodeling complex; Oct4, octamer-binding transcription factor 4; Sox2, sex-determining region Y-box 2; TERT, telomerase reverse transcriptase; DNMT1, DNA methyltransferase 1; RB1, Retinoblastoma 1; BRD, bromodomain-containing protein; NOX1, nicotinamide adenine dinucleotide phosphate oxidase 1; ROS, reactive oxygen species; NF-κB, nuclear factor-κB; YAP1, Yes-associated protein 1.