The significance of epigenetics and precision medicine in the context of uncommon cancers, referred to as "rare cancers," is investigated in this chapter.A comprehensive review of the current literature on noncoding RNAs (ncRNAs), natural products, and clinical trials specific to uncommon cancers was conducted. The role of ncRNAs in tumor biology is elaborated, revealing their dual influence on tumor suppression and oncogenesis, alongside current therapeutic strategies targeting these molecules. Recent clinical trial outcomes were analyzed to assess therapeutic potentials and innovations. The role of epigenetic mechanisms in rare cancer development and treatment, particularly focusing on how natural products can modify epigenetic mechanisms, such as DNA methylation, histone modifications, and the regulation of ncRNAs, was discussed in detail. The chapter emphasizes the potential of these natural products as therapeutic agents, or "epi-drugs," in cancer prevention and treatment.
Epigenetic modifications function as central controllers of gene expression in cancer, coordinating crucial cellular activities that trigger the initiation and progression of the tumor, besides their importance in therapeutic response. These modifications can control the gene expression without changing the sequence of DNA. In colorectal cancer (CRC), these alterations involving DNA methylation, histone modifications, chromatin rearrangement, and noncoding ribonucleic acids play a significant role in the pathogenesis of CRC. Abnormal DNA methylation silences the tumor suppressor genes, meanwhile leading to the instability of the genome via reduction of the whole methylation. Specific methylation signatures, such as CpG islands, help in categorizing the subtypes of the tumor and predicting the clinical outcomes. In addition, histone-modifying enzymes, including enhancer of zeste homolog 2 and histone deacetylases, are frequently uncontrolled in cancer, leading to alterations in gene expression. Moreover, small regulatory ribonucleic acids such as microRNA-21 and microRNA-143 contribute to the complex networks that regulate cell survival and growth. Collectively, these epigenetic alterations trigger the transition from benign growth to malignant cancer by continuously suppressing crucial genes. Furthermore, the epigenetic markers can be detected in blood and stool specimens, offering promising tools for the early detection of cancer. The major obstacle in cancer treatment is the resistance to chemotherapy drugs, which is mainly caused by epigenetic modifications in cancer cells. Therefore, the new therapeutic ways target the modifications that occur in DNA methylation and histone, mostly in conjunction with conventional therapies. As the metabolites produced by the gut microbiome can alter the host epigenetics, they can promote cancer development. Promising technologies help in the concise proofreading of epigenetic marks, and advanced single-cell analysis is paving the way for personalized treatment approaches. This cutting-edge knowledge of epigenetic regulation mechanisms offers new prospects for enhancing diagnosis, prognosis, and targeted therapies in colorectal cancer.
There is an urgent need for reliable noninvasive indicators of the occurrence and course of liver disease. According to research conducted in recent decades, the risk scores for liver-related complications can be determined by utilizing the genetic and epigenetic components involved in the development of liver disease. This might potentially indicate the feasibility of implementing programs for target screening and monitoring of complications.Precision medicine may be used to treat liver illnesses, thanks to recent advancements in our knowledge of the epigenetics of liver cells. In a multicellular organism, each cell has a distinct phenotype, even if they all have the same genetics. Chromatin states determined by epigenetic processes are necessary for this heritable yet dynamic cell identity. Genetic, environmental, and metabolic factors that determine DNA accessibility to the transcriptional machinery governing gene expression and cellular states in various liver illnesses can alter the epigenomic landscapes unique to the liver. Noncoding RNAs (ncRNAs) are examples of the epigenetic regulation of chromatin. The coordinated actions of numerous epigenetic factors that modify nucleosome positioning and structure (remodelers), create epigenetic marks in DNA and histones (writers), identify and interpret the marks (readers), and eliminate these marks (erasers) preserve this epigenetic information.Here, we summarize the literature on how epigenetic changes contribute to the development of liver cancers. Along with talking about the potential of epigenetic therapy approaches, we also address their usefulness as epigenetic biomarkers for the diagnosis and prognosis of hepatocellular carcinoma.
Breast cancer remains a leading cause of cancer-related morbidity and mortality in women worldwide. While extensive research has focused on mutations in protein-coding genes, emerging evidence underscores the pivotal role of the noncoding genome-including long noncoding RNAs (lncRNAs), microRNAs (miRNAs), circular RNAs (circRNAs), and piwi-interacting RNAs (piRNAs)-in tumorigenesis, progression, and therapeutic resistance. These noncoding RNAs (ncRNAs) are regulated through diverse epigenetic mechanisms such as DNA methylation, histone modifications, and N6-methyladenosine (m6A) RNA methylation. Aberrant epigenetic modifications in noncoding regions can silence tumor suppressors or activate oncogenes, thereby reprogramming cellular behavior and contributing to breast cancer heterogeneity. High-throughput techniques like whole-genome bisulfite sequencing (WGBS), ATAC-seq, and ChIP-seq have facilitated the discovery of noncoding epimutations with clinical significance. Moreover, ncRNA-based epigenetic alterations are increasingly explored as diagnostic biomarkers, prognostic indicators, and therapeutic targets, particularly in subtype-specific contexts such as triple-negative breast cancer (TNBC) and HER2-positive tumors. Despite advances, challenges remain in interpreting functional noncoding elements and translating findings into clinical interventions. This chapter provides a comprehensive examination of the noncoding epigenome in breast cancer, highlighting current methodologies, molecular mechanisms, and translational potential while also identifying future directions needed to leverage noncoding epigenetics for personalized cancer care.
The human gut microbiome and noncoding RNAs (ncRNAs) represent interconnected regulatory networks that profoundly influence cancer development, particularly in gastrointestinal and endocrine-related malignancies. This chapter delineates the intricate interplay of microbiome-ncRNA crosstalk in the context of gastrointestinal and endocrine-related cancers.The chapter begins with a comprehensive overview of the taxonomic and functional landscape of the healthy adult gut microbiome. The gut microbiome, comprising trillions of microorganisms, plays a crucial role in endocrine regulation through hormone metabolism, synthesis of bioactive compounds, and modulation of immune responses, thereby establishing a critical crosstalk with the host endocrine system. Dysbiosis, or microbial imbalance, has been linked to endocrine dysfunction and the pathogenesis of various diseases, including gastrointestinal and endocrine-related cancers.We then elucidate the classifications of noncoding RNAs and their function as key molecular regulators in cellular communication, gene expression, and disease progression. NcRNAs contribute significantly to the development and progression of endocrine-related malignancies. The intricate crosstalk between the gut microbiome and host ncRNAs demonstrates how gut dysbiosis can disrupt host ncRNA expression patterns, thereby affecting oncogenic pathways, immune surveillance, and metabolic reprogramming linked to tumor initiation, progression, and metastasis. Conversely, host-derived ncRNAs, secreted into the gut lumen, can directly shape microbial gene expression. In this section, we explore how dysregulation of this axis contributes to carcinogenesis through the promotion of chronic inflammation, epithelial barrier dysfunction, and oncogenic signaling. Therapeutic strategies targeting this interplay, including probiotics, prebiotics, fecal microbiota transplantation, and dietary interventions, are introduced in the context of restoring microbial balance.This comprehensive chapter provides crucial insights into the molecular mechanisms governing microbiome-ncRNA interactions and their implications for cancer biology, offering new perspectives for therapeutic interventions in gastrointestinal and endocrine-related malignancies.
This work examined the integration of epigenetics and precision medicine in the management of various blood disorders, including anemias, antiphospholipid syndrome, hemochromatosis, hemophilia, leukemia, lymphoma, multiple myeloma, porphyria, thalassemia, thrombocytopenia, thrombocytosis, polycythemia, von Willebrand disease, and coagulopathy. It begins with an overview of key concepts and the significance of precision medicine in treating blood diseases, supported by current statistics. The role of noncoding RNAs (ncRNAs) is highlighted, detailing their mechanisms of action and clinical implications as potential biomarkers and therapeutic targets. Additionally, the chapter explores natural products used in personalized medicine, examining their sources, mechanisms, and successful case studies in blood disorders. A comprehensive review of recent clinical trials provides insights into the impact of innovative therapies and FDA approvals on treatment protocols, emphasizing the importance of combination therapies. Future directions address emerging research technologies such as clustered regularly interspaced short palindromic repeats (CRISPR) and ethical considerations surrounding genetic testing and patient consent. The synthesis of findings underscores the contributions of epigenetics and precision medicine to blood disease treatment, advocating for interdisciplinary research and ongoing education to enhance patient care and outcomes.
Polyphenols (PPs) are secondary metabolites that are present in more than 80% of plants. They possess a plethora of medicinal properties by modulating key pathological pathways, including epigenetics and those involved in oncogenesis or tumorigenesis. PPs have been shown to inhibit tumor cell proliferation, metastasis, and cancer cell resistance to chemotherapeutic medications. Their coadministration, either as plant-rich extracts or in advanced pharmaceutical formulations like nano-formulations, significantly impacts the tolerability, efficiency, and cytotoxicity of traditional chemotherapeutic drugs. Both clinical and preclinical studies, including in vitro and in vivo models, demonstrated the potent anticancer activity of PPs. Combining PPs with conventional chemotherapeutic agents has led to a significant improvement in the efficiency and safety index of these agents. Advances in PP nano-formulations have enhanced their bioavailability and therapeutic efficacy. The current chapter highlights the potential of PPs and recent advances in their formulation for targeting cancer.
Epigenetic regulation plays a central role in immune cell development, specialization, and memory formation by dynamically modifying DNA, histones, and RNA. These processes enable adaptation to environmental cues, precise pathogen responses, and maintenance of immune tolerance, while their disruption contributes to autoimmune, inflammatory, and cancer pathogenesis. DNA methylation, histone modifications, and noncoding RNA regulation shape the lineage and activation states of T cells, B cells, macrophages, and natural killer (NK) cells, with specific alterations linked to diseases, such as systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). Emerging insights also highlight roles for RNA modifications and exosome-mediated RNA transfer in immune activation, trained immunity, and antigen presentation. Advances in single-cell epigenomics, CRISPR-based editing, and RNA sequencing are driving the development of targeted therapies-such as DNA methyltransferase (DNMT) inhibitors, histone deacetylase (HDAC) inhibitors, RNA-based interventions, and exosome delivery systems-that aim to reprogram immune responses. Understanding immune cell epigenetics paves the way for precision immunotherapies tailored to patient-specific profiles, offering highly specific, effective treatments with minimal immune suppression.
Actin was first identified as a major muscle protein with two key activities: polymerization and ATPase. Although the significance of these activities in muscle contraction was unclear, subsequent cell biological studies revealed that actin is abundant also in non-muscle cells, where it drives dynamic remodeling through ATP-dependent treadmilling. Biochemical studies revealed that the polymerization coupled with ATP hydrolysis produces two distinct F-actin states: a stable ADP-Pi state and an unstable ADP state. The transition between the ADP-Pi and ADP states (i.e., Pi release) likely generates the free energy that drives treadmilling.In this chapter, we introduce our structural biological studies of these states and the mechanisms underlying their formation. Our F-actin model showed that polymerization induces a rotation between its two rigid domains, shifting actin from a twisted G-form to a flat F-form. We also resolved the cryo-EM structure of cofilin-decorated F-actin, in which actin adopts a distinct C-form. Analysis of PDB data classified actin structures into four conformations: G-, F-, C-, and O-forms, each linked to specific functions-G-form for nucleotide exchange, F-form for ATP hydrolysis, and C-form for filament severing. High-resolution F-form structures further elucidated the ATP hydrolysis pathway and the basis for the stability of the ADP-Pi state.Despite these advances, key questions remain. Although the global structure of F-form actin is identical across nucleotide states, its properties differ: ATP/ADP-Pi states are stable and cofilin-resistant, whereas the ADP state is prone to depolymerization and cofilin-mediated severing. We suggest that each state should be characterized by the distinct nature of conformational fluctuations from F-form back to G-form.
Striated muscle is composed of overlapping arrays of thick myosin filaments and thin actin filaments. The thick filaments are composed of myosin molecules, which are hexamers of two heavy chains and two pairs of light chains. The heavy chain has an N-terminal head domain and a C-terminal helical rod domain. The latter dimerises to form a two-stranded coiled-coil rod. The distal two-thirds of these rods aggregate in parallel to form the filament backbone, while the heads lie on the surface to facilitate interactions with actin. The molecules aggregate in an antiparallel manner in the centre of the A-band to form the so-called bare zone. The proximal one-third of the rod can swivel and thereby allow the myosin heads to interact with actin. The atomic structure of the head, determined in the 1990s, was a major milestone in the muscle field. Over the next three decades, great strides were made in cryo-electron microscope technology and software. This led to the high-resolution structure of the insect flight muscle thick filament, showing the structure of the myosin tails at 6 Å resolution and the structure of the heads. There has been great excitement recently with the high-resolution structures of relaxed cardiac muscle thick filaments showing details of all the important players: three types of myosin crowns and the paths of their tails, the structure and interactions of cMyBP-C and the structure of two unique forms of titin and its role in filament assembly. Hypertrophic cardiomyopathy, which results from mutations in sarcomeric proteins, especially myosin and cMyBP-C, is a major health burden and insight gained from the new studies will help to devise new therapies.
Amyloids play critical functional roles in biology, including microbial virulence, innate immunity, and cellular organization, broadening their traditional association with neurodegenerative and systemic diseases. This chapter explores the structural and functional plasticity of amyloids, emphasizing how a single protein sequence can adopt multiple fibrillar conformations, termed polymorphs, each with distinct biological outcomes. We synthesise recent high-resolution structural insights from cryo-EM, NMR, and microcrystallography that elucidate the polymorphic behaviour of amyloids in both pathogenic and functional contexts. Particular focus is placed on bacterial functional amyloids that stabilise biofilms and modulate host-pathogen interactions and on antimicrobial peptides that form reversible fibrils with cytotoxic or immune-stimulatory functions. We also highlight the emerging paradigm of amyloid-nucleic acid co-assemblies and their role in immune recognition, autoimmunity, and possibly the origin of life. By examining structure-function relationships across a broad evolutionary spectrum, we argue that amyloid polymorphism constitutes a general mechanism of biological regulation. Understanding how these fibrils shift between states, including cross-β, cross-α, nanotubular, or phase-separated condensates, offers insight into their dual roles in health and disease. This perspective repositions amyloids not merely as pathological end-products but as versatile, ancient scaffolds for structural adaptation and functional innovation.
Helix-helix interactions are mediated through highly designable interfaces within tertiary and quaternary structures of proteins and protein assemblies. The structural regularity of these interfaces suggests that ordered self-assembled structures could be constructed from implementation of these interactions between appropriately designed helical protomers. This review summarizes the current understanding of helix-helix interactions within different classes of naturally occurring α-helical protein filaments. The implications of this structural information for the de novo design of synthetic filamentous nanomaterials will be discussed with reference to examples in which these principles have been successfully implemented. A specific case study will focus on the designability of cross-α helical filaments, a recently discovered structural class in which the helical protomers are arranged in a perpendicular orientation with respect to the protofilament axis. This discussion will include an evaluation of the frequency of occurrence of cross-α interfaces in the PDB, the effectiveness of structural prediction from sequence information, and the potential for de novo design of interfaces that promote cross-α interactions.
Fibrillar collagens are the most abundant structural proteins in vertebrates, forming the backbone of connective tissues such as skin, bone, tendon, and cartilage. In bony fish (teleosts), fibrillar collagens exhibit unique genetic and biochemical properties that reflect a complex evolutionary history of this taxonomic group and its adaptation to diverse aquatic environments-from tropical to polar habitats. This review summarises the current understanding of the genetic organisation and biochemical characteristics of fibrillar collagens in bony fish. They show significant differences in amino acid composition to mammalian collagens, especially in cold-adapted species, where collagens display lower thermal stability and reduced hydroxyproline content relative to their mammalian counterparts.Advances in genomic, transcriptomic, and proteomic profiling have provided new perspectives on the molecular diversity and tissue-specific roles of collagen chains in teleosts. Furthermore, the biomedical potential of fish-derived collagens is receiving growing attention, particularly in biomaterials, wound healing, tissue engineering, and drug delivery systems, owing to their biocompatibility, low immunogenicity, and ease of extraction from byproducts of the fishing industry.By looking at molecular, structural, and applied perspectives, this review highlights the relevance of bony fish collagens as a subject of fundamental biological interest and as a valuable resource for biotechnological and biomedical innovation.
This chapter explores the role of fibrillar collagens, mainly collagen I, in developing fibrotic disorders associated with acute or chronic injuries. While collagen molecules' fundamental structure, composition, and intracellular biosynthesis steps remain similar in healthy and scar tissues, their extracellular architecture and physical properties significantly differ. These differences arise from the excessive production of collagen I and auxiliary proteins associated with collagen I folding and posttranslational modifications. As a result, the overaccumulation of collagen I-based fibrotic deposits creates a rigid mechanical environment that, through mechanotransduction, amplifies pro-fibrotic signaling in resident fibroblasts.In reviewing the literature, this chapter highlights key players that create, transmit, and sustain these signals, thereby perpetuating fibrosis. Given the growing recognition of mechanotransduction as a valid therapeutic target to limit fibrosis, this chapter also discusses strategies to inhibit different elements of this process. A significant challenge with these strategies is that both balanced and excessive scarring rely on the exact underlying mechanisms of scar tissue formation. Consequently, conventional anti-fibrotic agents may inadvertently impair the essential scarring needed to preserve tissue integrity after injury. Therefore, mechanotherapeutics that reduce collagen accumulation-driven scar stiffness represent a novel approach for developing more targeted anti-fibrotic therapies.
The coiled coil is one of the most widespread and versatile protein folding motifs and is involved in a vast array of biological functions. The study and design of these assemblies have been shaped by the development of specialised computational tools. This review charts the landscape of these in silico methods, beginning with the foundational sequence-based algorithms for coiled-coil prediction and classification, before moving to the powerful parametric methods that enable the generation of idealised, atomic-resolution structural models. We argue that while indispensable, these tools can promote a view of coiled coils as static, singular structures. Challenging this, we highlight the structural plasticity of coiled coils, the remarkable and increasingly evident ability of these assemblies to adopt multiple distinct conformations and dynamically switch between states. To understand the energetic and mechanistic principles governing this complex behaviour, we explore the crucial role of molecular dynamics (MD) simulations in providing atomistic insights that are inaccessible to static modelling. Finally, we look forward, considering how the next generation of coiled-coil bioinformatics must evolve to address these challenges to take advantage of the opportunities presented by the current explosion in genomic sequence data and the proliferation of AI-predicted protein structures.
Intermediate filaments (IFs) possess unique mechanical properties that distinguish them from actin filaments and microtubules. In particular, they exhibit high flexibility, pronounced extensibility, and complete stability during biochemical extractions from cells and tissues. These characteristics stem from their molecular structure, which is typical of fibrous proteins. A defining feature is the central ~300 amino acid long α-helical segment with a distinct hydrophobic sequence pattern, facilitating the formation of a parallel coiled-coil dimer. Under low ionic strength conditions, two such dimers interact via their basic amino-terminal domains with the acidic coiled-coil domains to form distinct, rod-like tetrameric complexes. Upon addition of salt, the tetramers first assemble laterally into full-width, unit-length filaments, which then anneal longitudinally into micrometer-long filaments with a characteristic, 10-nm diameter. Advanced experimental techniques enable us to measure piconewton forces and micrometer length scales. By combining, for example, optical tweezers or atomic force microscopy with sophisticated data analysis and numeric modeling, we have deepened our understanding of the structure-mechanics relationship in IFs, including their force-extension behavior and the low bending rigidity. These findings enable us to hypothesize about the mechanical roles of these filaments within the living cell and speculate about biomimetic, synthetic materials.
The world population is ageing rapidly. The over-60s now outnumber the under- 5s, and 1 in 6 people will be over 60 by 2030 (WHO). Collagen is a key structural component of many tissues and organs, and although a fraction of the collagenous component of tissues is remarkably long-lived, it progressively accumulates damage over a lifetime. The capacity for new collagen synthesis and post-translational modification is altered and dysregulated during ageing. The mature crosslinks that stabilise collagenous tissues can remain stable or increase with age, whereas age-related glycation end-products can increase and affect tissue biomechanics. At the fibrillar nanoscale, changes associated with ageing and disease influence fibril deformation and stress transfer in a tissue-specific manner. Age-related loss of collagen can be caused by proteolytic degradation, but normal collagen turnover is also affected by ageing and its dysregulation is detrimental to tissue homeostasis. Age-related accumulation of senescent cells may contribute to the aberrant turnover of collagen during ageing. Finally, collagen itself may hold the key to counteracting some of the detrimental effects of ageing, with ingested hydrolysed collagen peptides demonstrating beneficial effects on skin and the musculoskeletal system.
Intermediate filaments (IFs) are central to the mechanical integrity of metazoan cells and play critical roles in various fundamental cellular and multicellular processes, including cell motility, signal transduction, and wound healing. To perform their functions, IF proteins self-assemble into nanoscale biopolymers, each exhibiting unique properties that are finely tuned to their specific roles across different tissue types. However, the 3D structure of IFs has remained largely unresolved due to their intrinsic flexibility and polymorphism. This chapter reviews recent advances in the structural analysis of IFs, with a focus on vimentin IFs (VIFs), which are featuring a helical tube with a central luminal fiber. We discuss how AlphaFold-based modeling, chemical cross-linking data, and cryo-electron microscopy (cryo-EM) reconstructions have been integrated to generate a detailed structural model of VIFs, highlighting key features such as the helical symmetry of the filaments and the nature of the luminal fiber. Additionally, we explore potential sources of IF polymorphism and their implications for the analysis of IF structures.
