Ethical implications of epigenetics in the era of personalized medicine

Given the increasing research activity on epigenetics to monitor human diseases and its connection with lifestyle and environmental expositions, the field of epigenetics has attracted a great deal of interest also at the ethical and societal level. In this review, we will identify and discuss current ethical, legal and social issues of epigenetics research in the context of personalized medicine. The review covers ethical aspects such as how epigenetic information should impact patient autonomy and the ability to generate an intentional and voluntary decision, the measures of data protection related to privacy and confidentiality derived from epigenome studies (e.g., risk of discrimination, patient re-identification and unexpected findings) or the debate in the distribution of responsibilities for health (i.e., personal versus public responsibilities). We pay special attention to the risk of social discrimination and stigmatization as a consequence of inferring information related to lifestyle and environmental exposures potentially contained in epigenetic data. Furthermore, as exposures to the environment and individual habits do not affect all populations equally, the violation of the principle of distributive justice in the access to the benefits of clinical epigenetics is discussed. In this regard, epigenetics represents a great opportunity for the integration of public policy measures aimed to create healthier living environments. Whether these public policies will coexist or, in contrast, compete with strategies reinforcing the personalized medicine interventions needs to be considered. The review ends with a reflection on the main challenges in epigenetic research, some of them in a technical dimension (e.g., assessing causality or establishing reference epigenomes) but also in the ethical and social sphere (e.g., risk to add an epigenetic determinism on top of the current genetic one). In sum, integration into life science investigation of social experiences such as exposure to risk, nutritional habits, prejudice and stigma, is imperative to understand epigenetic variation in disease. This pragmatic approach is required to locate clinical epigenetics out of the experimental laboratories and facilitate its implementation into societ

Towards a more precise therapy in cancer : Exploring epigenetic complexity

The authors thank CERCA Programme/Generalitat de Catalunya for institutional support. Research at F.P.C lab is supported by by Gobierno Vasco/Eusko Jaurlaritza (IT-324-07) and by 2020 Framework Programme of the European Union (Euro-Cholangio-Net CA18122).A plethora of preclinical evidences suggests that pharmacological targeting of epigenetic dysregulation is a potent strategy to combat human diseases. Nevertheless, the implementation of epidrugs in clinical practice is very scarce and mainly limited to haematological malignancies. In this review, we discuss cutting-edge strategies to foster the chemical design, the biological rationale and the clinical trial development of epidrugs. Specifically, we focus on the development of dual hybrids to exploit multitargeting of key epigenetic molecules deregulated in cancer; the study of epigenetic-synthetic lethality interactions as a mechanism to address loss-of-function mutations, and the combination of epidrugs with other therapies such as immunotherapy to avoid acquired chemoresistance and increase therapy sensitivity. By exploring these challenges, among others, the field of epigenetic chemical biology will increase its potential for clinical benefit, and more effective strategies targeting the aberrant epigenome in cancer are likely to be developed both in haematological and solid tumours

Epigenetic mechanisms during ageing and neurogenesis as novel therapeutic avenues in human brain disorders

Ageing is the main risk factor for human neurological disorders. Among the diverse molecular pathways that govern ageing, epigenetics can guide age-associated decline in part by regulating gene expression and also through the modulation of genomic instability and high-order chromatin architecture. Epigenetic mechanisms are involved in the regulation of neural differentiation as well as in functional processes related to memory consolidation, learning or cognition during healthy lifespan. On the other side of the coin, many neurodegenerative diseases are associated with epigenetic dysregulation. The reversible nature of epigenetic factors and, especially, their role as mediators between the genome and the environment make them exciting candidates as therapeutic targets. Rather than providing a broad description of the pathways epigenetically deregulated in human neurological disorders, in this review, we have focused on the potential use of epigenetic enzymes as druggable targets to ameliorate neural decline during normal ageing and especially in neurological disorders. We will firstly discuss recent progress that supports a key role of epigenetic regulation during healthy ageing with an emphasis on the role of epigenetic regulation in adult neurogenesis. Then, we will focus on epigenetic alterations associated with ageing-related human disorders of the central nervous system. We will discuss examples in the context of psychiatric disorders, including schizophrenia and posttraumatic stress disorders, and also dementia or Alzheimer's disease as the most frequent neurodegenerative disease. Finally, methodological limitations and future perspectives are discussed.EU Joint Programme-Neurodegenerative Disease Research (JPND; EPI-AD Consortium)RecerCaixa Foundation, Federación Española de Enfermedades Raras (FEDER)Federación Española de Enfermedades Neuromusculares (ASEM)Fundación Isabel GemioAsociación Española Contra el Cáncer (AECC)Ministerio de Sanidad, Servicios Sociales e Igualda

The timeline of epigenetic drug discovery:from reality to dreams

The flexibility of the epigenome has generated an enticing argument to explore its reversion through pharmacological treatments as a strategy to ameliorate disease phenotypes. All three families of epigenetic proteins-readers, writers, and erasers- A re druggable targets that can be addressed through small-molecule inhibitors. At present, a few drugs targeting epigenetic enzymes as well as analogues of epigenetic modifications have been introduced into the clinic use (e.g. to treat haematological malignancies), and a wide range of epigenetic-based drugs are undergoing clinical trials. Here, we describe the timeline of epigenetic drug discovery and development beginning with the early design based solely on phenotypic observations to the state-of-the-art rational epigenetic drug discovery using validated targets. Finally, we will highlight some of the major aspects that need further research and discuss the challenges that need to be overcome to implement epigenetic drug discovery into clinical management of human disorders. To turn into reality, researchers from various disciplines (chemists, biologists, clinicians) need to work together to optimise the drug engineering, read-out assays, and clinical trial design

Discovery of novel DNA methylation biomarkers for non-invasive sporadic breast cancer detection in the Latino population

Altres ajuts: This study was supported by grants from the Agencia Nacional de Investigación e Innovación (ANII) (FMV_3_2011_1_5904 to MC), and Programa de Desarrollo de las Ciencias Básicas (PEDECIBA, to MC and BB).Human diversity is one of the main pitfalls in the development of robust worldwide biomarkers in oncology. Epigenetic variability across human populations is associated with different genetic backgrounds, as well as variable lifestyles and environmental exposures, each of which should be investigated. To identify potential non-invasive biomarkers of sporadic breast cancer in the Uruguayan population, we studied genome-wide DNA methylation using Illumina methylation arrays in leukocytes of 22 women with sporadic breast cancer and 10 healthy women in a case-control study. We described a panel of 38 differentially methylated CpG positions that was able to cluster breast cancer patients (BCP) and controls, and that also recapitulated methylation differences in 12 primary breast tumors and their matched normal breast tissue. Moving forward, we simplified the detection method to improve its applicability in a clinical setting and used an independent well-characterized cohort of 80 leukocyte DNA samples from BCP and 80 healthy controls to validate methylation results at specific cancer-related genes. Our investigations identified methylation at CYFIP1 as a novel epigenetic biomarker candidate for sporadic breast cancer in the Uruguayan population. These results provide a proof-of-concept for the design of larger studies aimed at validating biomarker panels for the Latin American population

Discovery of novel DNA methylation biomarkers for non‐invasive sporadic breast cancer detection in the Latino population

Human diversity is one of the main pitfalls in the development of robust worldwide biomarkers in oncology. Epigenetic variability across human populations are associated with different genetic backgrounds, as well as variable lifestyles and environmental exposures, each of which should be investigated. To identify potential non-invasive biomarkers of sporadic breast cancer in the Uruguayan population, we studied genome-wide DNA methylation using Illumina methylation arrays in leukocytes of 22 women with sporadic breast cancer and 10 healthy women in a case-control study. We described a panel of 38 differentially methylated CpG positions that was able to cluster breast cancer patients and controls, and that also recapitulated methylation differences in 12 primary breast tumors and their matched normal breast tissue. Moving forward we simplified the detection method to improve its applicability in a clinical setting, and used an independent well-characterized cohort of 80 leukocyte DNA samples from breast cancer patients and 80 healthy controls to validate methylation results at specific cancer-related genes. Our investigations identified methylation at CYFIP1 as a novel epigenetic biomarker candidate for sporadic breast cancer in the Uruguayan population. These results provide a proof-of-concept for the design of larger studies aimed at validating biomarker panels for the Latin American population

Hemp peptides (Cannabis sativa L.) modulate the neuro-inflammatory process via inflamasome

Plant proteins have generated great interest in recent years because they are a potential source of peptides with biological activity. In this sense, extensive protein hydrolysates with high degree of hydrolysis obtained by enzymatic hydrolysis are used in specialized feeding to prevent or treat chronic diseases. In this study, different hemp protein hydrolysates were used to test their neuroprotective effects on BV-2 microglial cells. Motivation: The current trend on organic farming and sustainability has increased interest in the cultivation of industrial hemp (Cannabis sativa L.) in recent years for its multiple applications in a wide range of sectors. The cultivation of industrial hemp, a fast-growing plant with low tetrahydrocannabinol (THC) < 0.2%, is considered sustainable because it does not require herbicide fertilizers or pesticides. Its seeds have a high nutritional value due to their richness in fatty acids, proteins, essential amino acids, carbohydrates, vitamins and minerals, as well as functional, due to their content in antioxidant, anti-inflammatory and neuroprotective bioactive compounds. Recent data link NLRP3 inflammation, a macromolecular complex, IL-1β , and IL-18, in the development and evolution of neurodegenerative diseases. Methods: From hemp seeds, a protein isolate was obtained and subsequently hydrolyzed with the enzymes Alcalase and Flavourzyme. Two hemp protein hydrolysates (HP20A, HP60A+15AF) were characterized and used in BV2 microglial cells previously stimulated with lipopolysacchaid (LPS), in order to evaluate their anti-inflammatory activity. Results: Both protein hydrolysates HP20A and HP60A+15AF showed a potential neuroprotective effect via inflamasome by suppressing the gene expression of IL-18 and IL-1β pro-inflammatory cytokines

The Genome-wide Methylation Profile of CD4+ T Cells From Individuals With Human Immunodeficiency Virus (HIV) Identifies Distinct Patterns Associated With Disease Progression

Background: Human genetic variation-mostly in the HLA and CCR5 regions-explains 25% of the variability in progression of HIV infection. However, it is also known that viral infections can modify cellular DNA methylation patterns. Therefore, changes in the methylation of CpG islands might modulate progression of HIV infection. Methods: 85 samples were analyzed: 21 elite controllers (EC), 21 HIV-infected subjects before combination antiretroviral therapy (cART) (viremic, 93,325 HIV-1 RNA copies/ml) and under suppressive cART (cART, median of 17 months, <50 HIV-1 RNA copies/ml), and 22 HIV-negative donors (HIVneg). We analyzed the methylation pattern of 485,577 CpG in DNA from peripheral CD4+ T lymphocytes. We selected the most differentially methylated gene (TNF) and analyzed its specific methylation, mRNA expression, and plasma protein levels in 5 individuals before and after initiation of cART. Results: We observed 129 methylated CpG sites (associated with 43 gene promoters) for which statistically significant differences were recorded in viremic vs HIVneg, 162 CpG sites (55 gene promoters) in viremic vs cART, 441 CpG sites (163 gene promoters) in viremic vs EC, but none in EC vs HIVneg. The TNF promoter region was hypermethylated in viremic vs HIVneg, cART, and EC. Moreover, we observed greater plasma levels of TNF in viremic individuals than in EC, cART, and HIVneg. Conclusions: Our study shows that genome methylation patterns vary depending on HIV infection status and progression profile and that these variations might have an impact on controlling HIV infection in the absence of cART

Methylation regulation of Antiviral host factors, Interferon Stimulated Genes (ISGs) and T-cell responses associated with natural HIV control

GWAS, immune analyses and biomarker screenings have identified host factors associated within vivoHIV-1 control. However, there is a gap in the knowledge about the mechanisms that regulate the expression of such host factors. Here, we aimed to assess DNA methylation impact on host genome in natural HIV-1 control. To this end, whole DNA methylome in 70 untreated HIV-1 infected individuals with either high (>50,000 HIV-1-RNA copies/ml, n = 29) or low (<10,000 HIV-1-RNA copies/ml, n = 41) plasma viral load (pVL) levels were compared and identified 2,649 differentially methylated positions (DMPs). Of these, a classification random forest model selected 55 DMPs that correlated with virologic (pVL and proviral levels) and HIV-1 specific adaptive immunity parameters (IFNg-T cell responses and neutralizing antibodies capacity). Then, cluster and functional analyses identified two DMP clusters: cluster 1 contained hypo-methylated genes involved in antiviral and interferon response (e.g.PARP9,MX1, andUSP18) in individuals with high viral loads while in cluster 2, genes related to T follicular helper cell (Tfh) commitment (e.g.CXCR5andTCF7) were hyper-methylated in the same group of individuals with uncontrolled infection. For selected genes, mRNA levels negatively correlated with DNA methylation, confirming an epigenetic regulation of gene expression. Further, these gene expression signatures were also confirmed in early and chronic stages of infection, including untreated, cART treated and elite controllers HIV-1 infected individuals (n = 37). These data provide the first evidence that host genes critically involved in immune control of the virus are under methylation regulation in HIV-1 infection. These insights may offer new opportunities to identify novel mechanisms ofin vivovirus control and may prove crucial for the development of future therapeutic interventions aimed at HIV-1 cure. Author summary The infection with the human immunodeficiency virus (HIV), as for other viral infections, induce global DNA Methylation changes in the host genome. Herein, we identified for first time the methylation impact on host genome in untreated HIV-1 infection with different degrees ofin vivovirus control. Specifically, we observed that individuals with a better HIV-1 control showed a hypermethylation of genes associated with antiviral and interferon pathways and the hypomethylation of genes associated with the differentiation process of T follicular helper cells. Interestingly, these epigenetic imprints in host genome were strongly correlated with virus content and HIV-specific T cell responses. Therefore, we propose DNA Methylation as the regulation mechanism of host genes involved in immune HIV-1 control that could interfere in the efficacy of cure strategies. We also highlight the importance of DNA Methylation to regulate immune responses not only in HIV-1 but also in chronic infections or other pathologic situations associated with a sustained activation of the immune system

Methylation regulation of Antiviral host factors, Interferon Stimulated Genes (ISGs) and T-cell responses associated with natural HIV control

GWAS, immune analyses and biomarker screenings have identified host factors associated with in vivo HIV-1 control. However, there is a gap in the knowledge about the mechanisms that regulate the expression of such host factors. Here, we aimed to assess DNA methylation impact on host genome in natural HIV-1 control. To this end, whole DNA methylome in 70 untreated HIV-1 infected individuals with either high (>50,000 HIV-1-RNA copies/ml, n = 29) or low (<10,000 HIV-1-RNA copies/ml, n = 41) plasma viral load (pVL) levels were compared and identified 2,649 differentially methylated positions (DMPs). Of these, a classification random forest model selected 55 DMPs that correlated with virologic (pVL and proviral levels) and HIV-1 specific adaptive immunity parameters (IFNg-T cell responses and neutralizing antibodies capacity). Then, cluster and functional analyses identified two DMP clusters: cluster 1 contained hypo-methylated genes involved in antiviral and interferon response (e.g. PARP9, MX1, and USP18) in individuals with high viral loads while in cluster 2, genes related to T follicular helper cell (Tfh) commitment (e.g. CXCR5 and TCF7) were hyper-methylated in the same group of individuals with uncontrolled infection. For selected genes, mRNA levels negatively correlated with DNA methylation, confirming an epigenetic regulation of gene expression. Further, these gene expression signatures were also confirmed in early and chronic stages of infection, including untreated, cART treated and elite controllers HIV-1 infected individuals (n = 37). These data provide the first evidence that host genes critically involved in immune control of the virus are under methylation regulation in HIV-1 infection. These insights may offer new opportunities to identify novel mechanisms of in vivo virus control and may prove crucial for the development of future therapeutic interventions aimed at HIV-1 cure