Transposable elements (TEs), or mobile genetic elements, are fragments of DNA capable of moving from one genomic location to another. Traditionally, transposons have been considered selfish genetic elements because they increase their copy number by jumping into new genomic locations and causing genomic instability. In mammals, TEs make up a substantial portion of the genome, far exceeding the fraction occupied by protein-coding genes or regulatory elements such as promoters or enhancers, but only a small fraction is still able to mobilize. Additionally, in most adult cells, TE expression is largely silenced by epigenetic mechanisms and other pathways that protect the genome from the deleterious consequences of TE expression. However, during gametogenesis and early development, epigenetic reprogramming creates a window in which TEs can be expressed. Throughout evolution, host genomes have repurposed transposon-derived sequences to exert a function in a process known as co-option. Here, we summarize how TE expression is regulated and can be harnessed for the host's benefit, with a particular focus on the co-option of TEs during gametogenesis and early development, and present current evidence for their extensive regulatory roles.
Interferons are key mediators of antiviral defense. They enable infected cells and specialized immune populations to mount rapid transcriptional responses that restrict viral replication and support immune activation. Type I and type III interferons share many antiviral properties, but their effects are determined by distinct receptor distributions, signaling dynamics, and tissue localization. While both families contribute to protection against infection, this chapter focuses primarily on the regulation and function of type I interferons. The induction of interferons depends on the activation of pattern recognition receptors that detect viral nucleic acids and trigger signaling cascades involving IRF and NF-κB transcription factors. These pathways control tightly regulated transcriptional and epigenetic programs that drive interferon gene expression and the induction of interferon-stimulated genes. Balanced regulation is essential, as excessive or persistent signaling can cause immunopathology and chronic inflammation. Genetic variation in interferon pathways influences susceptibility to viral infections, and defects in interferon regulation contribute to several monogenic interferonopathies. Plasmacytoid dendritic cells are a major source of type I interferons and illustrate the complexity of cellular specialization in antiviral defense. Understanding these mechanisms is essential for the development of therapies that enhance antiviral protection or limit pathogenic inflammation in chronic infections and autoimmune disease.
This chapter reviews the current understanding of the role of transposable elements (TEs) in the aging process. TEs represent a significant proportion of mammalian genomes and, far from being "junk DNA", they harbor important functions as regulators of gene expression and important drivers of evolution. Their classification, epigenetic mechanisms that control their silencing, and the evidence for their progressive activation during physiological aging across multiple species are discussed.Aging is associated with a global loss of heterochromatin, which triggers TE derepression, and unleashes two major pathological consequences. First, the increased activity of these elements generates genomic instability through insertional mutagenesis, DNA damage, and changes in genome organization. Second, TE-derived nucleic acids are recognized by DNA sensors such as cGAS-STING and RNA sensors including RIG-I and MDA5, perpetuating interferon responses that contribute to the age-associated functional decline. Diverse therapeutic strategies to control TE dysregulation are presented, including reverse transcriptase inhibitors (NRTIs), lifestyle interventions, genetic approaches, and SIRT6 activation. These interventions have demonstrated efficacy in extending lifespan, suppressing TE expression, reversing inflammatory phenotypes, ameliorating age-related decline, and restoring TE epigenetic silencing in experimental models. Finally, the significance of TE-based biomarkers is highlighted, emphasizing their vital role as both effectors and indicators of biological age and their utility in assessing disease risk. Together, these findings position TE dysregulation as a fundamental aging mechanism and a promising therapeutic target for promoting healthy aging.
Transposable Elements (TEs) have the ability to transpose, and have populated all known eukaryotic genomes to date. Nowadays, their role in many aspects of biology, from population diversity to gene regulatory networks is well recognized. OMICS technologies, thanks to their genome-wide scale, provide an unparalleled resource to understand TE biology. However, due to their repetitive nature, TE analysis is not routinely carried out. In this chapter, I will provide the basic theoretical framework that will allow researchers to gain a first understanding of TEs without the need of significant alteration to established analysis pipelines. Then, I will present an overview on how TE analyses have been carried out for different OMICS data, as well as advantages and disadvantages on these approaches. Collectively, this chapter will provide the necessary background to explore TE contribution, so prospective researchers continue to reveal the multifaceted role of TEs in healthy and disease biology.
Transposable elements (TEs), once dismissed as genomic "junk," are now recognized as major forces shaping the architecture, function, and evolution of the nervous system. Among them, retrotransposons-particularly Long Interspersed Nuclear Elements (LINEs) play a dual role as both architects of neuronal diversity and saboteurs of genomic integrity. During neurodevelopment, transient retrotransposon activation contributes to somatic mosaicism, activity-dependent transcription, and synaptic plasticity, thereby enhancing cognitive adaptability. However, the same mechanisms that promote neuronal complexity render the brain vulnerable to aging and disease. Epigenetic erosion during senescence leads to derepression of LINEs and endogenous retroviruses, triggering genomic instability and neuroinflammation through the cGAS-STING pathway. Such "retrotransposon storms" are increasingly linked to neurodegenerative disorders, notably Alzheimer's disease, where tau- and Aβ-driven chromatin relaxation facilitates TE reactivation. The chapter integrates evidence from molecular, cellular, and translational research, highlighting therapeutic opportunities, from reverse transcriptase inhibitors like lamivudine to epigenetic and innate immune modulators, that aim to restore genomic homeostasis. Understanding retrotransposons as both evolutionary catalysts and pathological triggers reframes their role in brain biology and positions them as novel therapeutic targets in aging and neurodegeneration.
Transposable elements (TEs) are mobile DNA sequences that have played a central role in shaping the human genome. Among them, LINE-1 (L1) elements are particularly relevant in cancer, as most reported somatic activity originates from them. Under normal circumstances, L1 activity is tightly regulated at multiple stages of its life cycle; however, already early in cancer development, this control can be disrupted by global hypomethylation, TP53 inactivation, and chromatin deregulation, among other factors, allowing L1 elements to become transcriptionally active and mobile. Somatic L1 retrotransposition is particularly abundant in cancers of epithelial origin, most notably in esophageal, head and neck, colorectal, and lung squamous cell carcinomas. The resulting L1 insertions can disrupt genes, alter regulatory landscapes, and generate large chromosomal rearrangements, contributing to genomic instability. Most of these effects are driven by a small subset of highly active "hot" L1 elements segregating in the human population. Beyond their mutagenic potential, TE-derived transcripts and proteins can activate innate immune pathways, linking retrotransposon activity to cancer immunity. These tumor-type-specific patterns of L1 activity and their diverse genomic consequences are opening new avenues for leveraging TE activation as a biomarker, actionable therapeutic target, and modulator of the tumor immune microenvironment.
Autoimmune diseases represent a complex class of disorders characterized by the immune system's aberrant attack on self-tissues, driven by intricate genetic and environmental factors. Long noncoding RNAs (lncRNAs), a diverse class of transcripts exceeding 200 nucleotides in length and lacking protein-coding capacity, have emerged as pivotal regulators of gene expression, chromatin architecture, and immune cell function. Here, we review literature in autoimmune disease pathogenesis and the role of lncRNAs, particularly in the immune system. We also provide a summary of recent advances elucidating the multifaceted roles of lncRNAs in autoimmune pathogenesis. This review underscores the expanding significance of lncRNAs in immunogenetics and autoimmune biology, offering new avenues for research and clinical intervention.
Recent discoveries in the field of epigenetic regulation have shed light on the intricate processes of immune cell activation, differentiation, and function in response to threats. Epigenetics connects genetic and environmental factors and includes DNA methylation, histone post-translational modifications and the regulation of chromatin accessibility by non-coding RNAs controlling constitutive or inducible gene transcription. These mechanisms coordinate the activation or suppression of immune cells via specific transcriptional programmes. In particular, epigenetic marks at the sites of lineage-specific transcription factors, as well as the maintenance of cell-type-specific epigenetic modifications, dictate cell differentiation, cytokine production and functional ability following repeated exposure to antigens in memory T cells. Furthermore, the epigenetic and metabolic reprogramming that occurs during a primary innate immune response, results in enhanced responses to secondary challenges. A complete understanding of the epigenetic basis of immune cell differentiation and cellular stability will clarify pathological dysregulation and help delineate new therapeutic strategies for targeting immune disorders.
Leukocytes are typically migratory immune cells, and their migration is of critical immunological importance. In this context, chemokines and their receptors play a dynamic role in regulating the functions of leukocytes within the immune system, since they drive leukocytes into and out of blood and lymphatic vessels and direct their interstitial movement and positioning. Chemokines constitute a large family of cytokines that primarily regulate immune cell migration through the binding to chemokine receptors expressed on the surface of leukocytes. They are expressed by both immune and non-immune cells, and their activity is tightly regulated at several levels from transcription to secretion and distribution. Conventional chemokine receptors are G protein-coupled receptors (GPCR) found mainly in immune cells that can modulate the immune response activation by the initiation of a signaling cascade. On the contrary, atypical chemokine receptors act as decoy receptors and regulate chemokine levels in the blood. Together, chemokines and their receptors form the chemokine system, a complex network with high redundance and promiscuity. Dysregulation of this system can contribute to various disorders that have an immune or inflammatory component mediated by chemokine-directed leukocyte migration, such as chronic inflammatory and neurodegenerative disorders. Thus, in this chapter I focused on the role of chemokines and their receptors under physiological conditions and on their implication in disorders like multiple sclerosis, Parkinson's Disease and Alzheimer's Disease, in which neuroinflammation caused by the infiltration of these immune cells into the CNS and their activation plays a key role in the development of the pathologies.
Long non-coding RNAs (lncRNAs) have emerged as critical regulators of immune and inflammatory responses. Recent studies have highlighted the involvement of lncRNA in several inflammatory pathways such as NF-κB, MAPK, and JAK/STAT, where lncRNAs control processes like cytokine expression, transcription factor activation, nuclear translocation, and chromatin remodeling. They modulate the proliferation and differentiation of immune cells, including macrophages, dendritic cells, and T lymphocytes, by interacting with microRNAs, transcription factors, signaling proteins, and chromatin modifiers. They also affect the inflammatory response of non-immune cells, such as epithelial and endothelial cells. These multifaceted roles position lncRNAs as master regulators of inflammation, with their dysregulation contributing to the development and progression of various inflammatory diseases. Understanding their context-specific functions opens new avenues for therapeutic intervention and biomarker development.
The JAK-STAT signaling pathway is essential for regulating pro-inflammatory and immune responses across various cell types. Its involvement in inflammation has linked it to the pathogenesis of numerous autoimmune and inflammatory diseases. Genome-wide association studies have identified associations between JAK-STAT pathway genes and increased susceptibility to conditions such as type 1 diabetes, celiac disease, and multiple sclerosis. In recent years, this pathway has gained attention as a promising therapeutic target, leading to the development and clinical testing of several JAK-STAT inhibitors aimed at modulating immune-mediated inflammation. Despite notable progress in therapeutic modulation of the pathway, challenges remain in developing highly specific and effective drugs. Continued research is necessary to improve the precision and efficacy of treatments targeting the JAK-STAT pathway for autoimmune and inflammatory disorders.
The post-genomic era has ushered in a transformative shift in biomedical research, driven by the integration of multi-omics technologies and advanced computational tools. While genome-wide association studies (GWAS) have identified thousands of variants linked to complex traits and diseases, the majority of these lie in non-coding regions, where their functional roles remain elusive. This chapter explores how fine-mapping, functional genomics, and systems biology are converging to bridge this gap, moving from statistical associations to mechanistic insights. Using celiac disease as a model, we illustrate how genomic, transcriptomic, epigenomic, and proteomic data can be harmonized to identify causal variants, prioritize candidate genes, and map regulatory networks that drive disease pathogenesis. We highlight the power of fine-mapping in refining GWAS signals and the importance of integrating chromatin accessibility, QTL colocalization, and single-cell omics to contextualize genetic risk within specific cellular environments. The chapter also discusses the promise of polygenic risk scores, the role of metabolomics in capturing functional phenotypes, and the emergence of single-cell and spatial technologies in revealing disease heterogeneity. Despite these advances, challenges remain-including data heterogeneity, computational complexity, and the underrepresentation of non-European populations in genomic studies. Addressing these issues will be critical for ensuring the equity and clinical utility of precision medicine. Ultimately, this chapter underscores the transformative potential of translational genomics. By connecting genetic variation to molecular function and clinical outcome, multi-omics approaches are paving the way for more predictive, preventive, and personalized healthcare-particularly in the context of autoimmune and other complex diseases.
Coeliac disease (CD) is a chronic immune-mediated inflammatory disorder triggered by dietary gluten ingestion in genetically predisposed individuals. While gluten-specific T cells and HLA-DQ2/DQ8 alleles are critical to the disease onset, they account for less than half of the genetic heritability, underscoring the complexity of CD's genetic underpinnings. Genome-Wide Association Studies (GWAS) and next-generation sequencing have identified 42 non-HLA loci associated with CD risk, yet the molecular mechanisms underlying these associations remain largely unexplored. Notably, most disease-associated single nucleotide polymorphisms (SNPs) associated with CD are located in non-coding genomic regions, highlighting the regulatory potential of these variants. Emerging evidence demonstrates that non-coding RNAs (ncRNAs), particularly microRNAs and long non-coding RNAs, play crucial roles in gene regulation and disease development. Recent advances in transcriptomics have revealed new transcribed regions of the genome, shedding light on the functional significance of previously unannotated sequences. This review discusses the contribution of non-coding SNPs located in regulatory RNA regions to CD development, emphasizing the role of long non-coding RNAs and their potential as therapeutic targets.
Throughout human history, pathogens have exerted great pressure on human genome that have defined susceptibility to both infectious and autoimmune diseases. This is possible because both type of conditions share susceptibility loci. The emergence of novel technologies that improves the genome analysis has greatly enhanced our ability to characterize in deeper the genetic architecture of human susceptibility to infectious diseases and autoimmune conditions. These genetic data sets identify outstanding informative overlaps that point to genetic modulation of immune function and inflammatory responses that affects both types of conditions. In this work, we revised single nucleotide polymorphisms and other genetic variations shared between these two categories of disease.
The intestinal epithelium serves as a critical mechanical barrier against potentially pathogenic bacteria and their antigens while maintaining immune homeostasis and facilitating nutrient and water absorption. In the gut, T cells undergo a multitude of highly specialized differentiation processes which are influenced by the unique microenvironment. Several studies reveal that intestinal epithelial cells (IECs) not only provide signals that shape T cell responses but also express a variety of factors that modulate T cell activity, such as cytokines, chemokines, and antigen-presenting molecules. The crosstalk between T cells and intestinal epithelium is necessary to grant a delicate immune balance to prevent excessive inflammation while assuring tolerance towards commensal microbial communities. Disruption of this line of communication can be deleterious since it could lead to immune-inflammatory disorders such as inflammatory bowel disease (IBD) and other disorders such as colorectal cancer. In recent years, advanced genomic and transcriptomic technologies have partially untangled the regulatory networks underlying this interaction. Understanding how the mechanisms governing the regulation of the interaction between T cells and IECs offers potential therapeutic hints for enhancing mucosal immunity and treating related diseases affecting gastrointestinal health. This chapter explores the key cellular players of mucosal immunity and the importance of epithelial-T cell interactions for immune regulation and potential therapeutic applications.
Complex traits, characterized by their reliance on multiple genetic variants and intricate environmental influences, present a unique challenge in the field of genetics. At the core of complex traits lies the interaction between numerous genetic variants-often polygenic in nature-and their regulation through epigenetic mechanisms. These mechanisms, which include DNA methylation, histone modification, and non-coding RNA activity, play a crucial role in gene expression and can significantly influence phenotypic outcomes. By examining how genetic and epigenetic elements interact, we can gain insight into the biological processes that underlie variation in complex traits. Ultimately, this chapter seeks to provide a comprehensive framework for understanding the multifaceted relationships between genetic and epigenetic factors in complex traits. By unraveling these interactions, we hope to pave the way for future research that can inform strategies for improving health outcomes and clinical practices.
Obesity is increasingly recognized not only for its systemic health impacts but also for its association with visual defects and eye diseases. This chapter explores the relationship between obesity and ocular health, highlighting the mechanisms by which metabolic dysregulation influences visual outcomes. Obesity exacerbates risk factors such as hypertension, dyslipidemia, and insulin resistance, which compromise retinal and optic nerve health. Conditions like diabetic retinopathy, age-related macular degeneration, and glaucoma are discussed in the context of obesity-related inflammation, oxidative stress, and altered vascular function, focusing on the retina as one of the body's most metabolically demanding tissues. Key pathways include adipose-derived cytokines that disrupt retinal homeostasis, and the effects of insulin resistance on retinal cells and vasculature. Furthermore, this chapter covers emerging evidence on the advances of genetic factors linking diabetic retinopathy to retinal impairments. By elucidating these interactions, we aim to provide insight into preventive and therapeutic strategies that could mitigate vision loss among individuals with obesity.
Food cravings, an intense desire to consume specific foods, are a complex interplay of cognitive, emotional, behavioral, physiological, and cultural factors. Although prevalent across genders, food cravings are more frequent and intense in women, with hormonal fluctuations-particularly during the menstrual cycle and pregnancy-playing a significant role. Pregnancy, marked by profound hormonal and physiological shifts, often heightens cravings, likely as a response to the increased metabolic needs of both mother and fetus. However, the tendency to crave high-calorie, palatable foods during this time can lead to excessive weight gain, presenting potential risks to both maternal and fetal health. This chapter examines the neural mechanisms underlying altered eating behaviors during pregnancy and their role in triggering food cravings. We discuss the health implications of disrupted eating patterns in pregnancy, emphasizing the need for further research to advance understanding of female-specific neurobiology and to develop targeted interventions that support healthy eating behaviors, ultimately improving maternal and offspring health outcomes.
Prader-Willi syndrome (PWS) is a complex genetic disorder arising from abnormalities on chromosome 15q11.2-q13, characterized by distinct physical, cognitive, and behavioral features that evolve across the lifespan. Early manifestations include severe hypotonia, feeding difficulties, and failure to thrive in infancy, progressing to hyperphagia, obesity, intellectual disabilities, and behavioral challenges in later stages. Additional features include growth hormone deficiency, short stature, delayed puberty, and other endocrine abnormalities. Genetic advances have illuminated the role of imprinted genes, such as SNORD116, in driving the syndrome's core features, offering insights into its variability and severity. Emerging research on targeted pathways, including oxytocin and ghrelin signaling, holds promise for innovative treatments addressing hyperphagia and behavioral symptoms. This chapter provides a comprehensive overview of PWS's clinical features, natural history, and molecular underpinnings, underscoring the importance of early diagnosis, multidisciplinary care, and precision medicine in optimizing outcomes and enhancing the quality of life for individuals with PWS.
Genetics is a significant risk factor for developing type 2 diabetes, with a family history conferring a 1.5-3-fold increased risk. Intriguingly, this heritable risk is higher when the affected parent is the mother, suggesting a potential role of mitochondrial genetics -maternally inherited DNA - in diabetes pathogenesis, a hypothesis this chapter will explore. While obesity mediates some of the genetic risk of type 2 diabetes, the chapter and will focus on genetic influences on diabetes independent of obesity. Mechanistically, genetic variants directly or indirectly contribute to insulin resistance across key tissues, including liver, muscle and adipose tissue. This insulin resistance prevents the liver from efficiently suppressing glucose production in response to insulin and impairs glucose uptake in muscle during postprandial states. Insulin resistance is driven by complex interactions between the genome and environmental, which can, in turn, influence gene expression and contribute to worsening of metabolic dysfunction. This chapter examines how tissue-specific genetic changes drive insulin resistance in individual organs and how these localized dysfunctions contribute to the broader, multi-organ metabolic dysfunction that characterize type 2 diabetes.
