Involvement of histone methylation in the regulation of neuronal death

Neuronal death occurs in various physiological and pathological processes, and apoptosis, necrosis, and ferroptosis are three major forms of neuronal death. Neuronal apoptosis, necrosis, and ferroptosis are widely identified to involve the progress of stroke, Parkinson’s disease, and Alzheimer’s disease. A growing body of evidence has pointed out that neuronal death is tightly associated with expression of related genes and alteration of signaling molecules. In addition, recently, epigenetics has been increasingly focused on as a vital regulatory mechanism for neuronal apoptosis, necrosis, and ferroptosis, providing a new direction for treating nervous system diseases. Moreover, growing researches suggest that histone methylation or demethylation is involved in the processes of neuronal apoptosis, necrosis, and ferroptosis. These researches may imply that studying the potential roles of histone methylation is essential for treating the nervous system diseases. Here, we review potential roles of histone methylation and demethylation in neuronal death, which may give us a new direction in treating the nervous system diseases. (AU)

Histone methylation in pre-cancerous liver diseases and hepatocellular carcinoma: recent overview

Hepatocellular carcinoma (HCC) is the prevalent form of liver cancer in adults and the fourth most common cause of cancer-related death worldwide. HCC predominantly arises in the context of cirrhosis as a result of chronic liver disease, injury and inflammation. Full-blown HCC has poor prognosis because it is highly aggressive and resistant to therapy. Consequently, interventions that can prevent or restrain HCC emergence from pre-cancerous diseased liver are a desirable strategy. Histone methylation is a dynamic, reversible epigenetic modification involving the addition or removal of methyl groups from lysine, arginine or glutamine residues. Aberrant activity of histone methylation writers, erases and readers has been implicated in several cancer types, including HCC. In this review, we provide an overview of research on the role of histone methylation in pre-cancerous and cancerous HCC published over the last 5 years. In particular, we present the evidence linking environmental factors such as diet, viral infections and carcinogenic agents with dysregulation of histone methylation during liver cancer progression with the aim to highlight future therapeutic possibilities (AU)

Extracellular histones trigger oxidative stress-dependent induction of the NF-kB/CAM pathway via TLR4 in endothelial cells

Extracellular histones have been reported to aggravate different pathophysiological processes by increasing vascular permeability, coagulopathy, and inflammation. In the present study, we elucidate how extracellular histones (10–100 µg/mL) concentration dependently increase cytosolic reactive oxygen species (ROS) production using human umbilical vein endothelial cells (HUVECs). Furthermore, we identify cyclooxygenase (COX) and NADPH oxidase (NOX) activity as sources of ROS production in extracellular histone-treated HUVEC. This COX/NOX-mediated ROS production is also involved in enhanced NF-kB activity and cell adhesion molecules (VCAM1 and ICAM1) expression in histone-treated HUVEC. Finally, by using different toll-like receptor (TLR) antagonists, we demonstrate the role of TLR4 in CAMs overexpression triggered by extracellular histones in endothelial cells. In conclusion, our data suggest that through TLR4 signaling, extracellular histones increase endothelial cell activation, a mechanism involving increased COX- and NOX-mediated ROS. These findings increase our understanding on how extracellular histones enhance systemic inflammatory responses in diseases in which histone release occurs as part of the pathological processes. (AU)

Molecular and clinical characterization of H3 K27M-mutant “non-midline” glioblastoma: A case report and literature review / Estudio molecular y presentación clínica del glioblastoma con mutación H3 K27M «no de línea media»: descripción de un caso y revisión de la literatura

The WHO classification of tumors of the CNS in 2016 defined “diffuse midline glioma, H3 K27M-mutant” as a new tumor entity locating in the CNS midline. However, the H3 K27M-mutation in “non-midline” glioblastoma are rare and their characteristics have been rarely reported. A 16-year-old girl presented a hyper-intense lesion at her left temporal stem on T2WI, FLAIR and DWI. Biopsy was performed and molecular pathological diagnosis was glioblastoma with H3 K27M-mutant. Accordingly, the possibility of H3 K27M-mutant should be examined not only for diffuse glioma without IDH mutation that develops at a midline location, but also in non-midline locations (AU)

La clasificación de la OMS de los tumores del SNC en 2016 definió el «glioma difuso de la línea media, H3 K27M-mutante» como una nueva entidad tumoral que se localiza en la línea media del SNC. Sin embargo, la mutación H3 K27M en el glioblastoma «no de línea media» es infrecuente y sus características han sido raramente reportadas. Una niña de 16 años presentó una lesión hiperintensa en el tronco temporal izquierdo en T2WI, FLAIR y DWI. Se realizó una biopsia y el diagnóstico patológico molecular fue de glioblastoma con mutación H3 K27M. En consecuencia, la posibilidad de mutaciones H3 K27M debe examinarse no sólo en el caso de los gliomas difusos que se desarrollan en una localización de la línea media, sino también en gliomas sin mutación de IDH en localizaciones que no son de la línea media entre los pacientes (AU)

The value of Phosphohistone H3 as a cell proliferation marker in oral squamouscell carcinoma. A comparative study with Ki-67 and the mitotic activity index

Background: The Phosphohistone H3 (PHH3) antibody is recognized as a biomarker of cell proliferation, specificfor cells in mitosis, of prognostic value in different malignant neoplasms, however it has been poorly studied inoral squamous cell carcinoma (OSCC). The main objective of this study was to evaluate the immunoexpression ofthe PHH3 in the OSCC, through the correlation with the immunoexpression of Ki-67, the mitotic activity index(MAI), histological grading, clinical-morphological parameters and the rate of survival.Material and Methods: The study sample consisted of 62 cases of OSCC diagnosed in the Pathological AnatomyLaboratory of the Faculty of Dentistry, University of the Republic (Uruguay). In each of them, an immunohistochemical technique was performed for Ki-67 and PHH3 (serine 10) antibodies. Image J software was used for theMAI and biomarker quantification, defining the percentage of positivity and mitotic figures per 1000 tumor cells.Results: a significant association was obtained between the expression of PHH3 (p 0.016) and MAI (p 0.031) withsurvival time. However, no similar relationship was found with Ki-67 (p 0.295). Although it was confirmed astatistical association between histological grade and Ki-67 immunoexpression (p 0.004), PHH3 did not show asimilar relationship (p 0.564).Conclusions: It was confirmed the role of the PHH3 antibody as a biomarker of mitotic figures in OSCC and as apotential marker of cell proliferation. It is noteworthy that this is one of the first works that evaluates a possiblerelationship between the expression of this antibody and survival in OSCC. (AU)

Emerging roles of JMJD3 in cancer

Histone lysine methylation plays a key role in gene activation and repression. The trimethylation of histone H3 on lysine-27 (H3K27me3) is a critical epigenetic event that is controlled by Jumonji domain-containing protein-3 (JMJD3). JMJD3 is a histone demethylase that specifically removes methyl groups. Previous studies have suggested that JMJD3 has a dual role in cancer cells. JMJD3 stimulates the expression of proliferative-related genes and increases tumor cell growth, propagation, and migration in various cancers, including neural, prostate, ovary, skin, esophagus, leukemia, hepatic, head and neck, renal, lymphoma, and lung. In contrast, JMJD3 can suppress the propagation of tumor cells, and enhance their apoptosis in colorectal, breast, and pancreatic cancers. In this review, we summarized the recent advances of JMJD3 function in cancer cells.

The progress of research on histone methylation in ischemic stroke pathogenesis

Stroke, also known as cerebral stroke or cerebrovascular accident, refers to acute ischemic or hemorrhagic encephalopathy caused by a disturbance to cerebral blood flow. Ischemic stroke is the most common type of cerebral stroke, accounting for approximately 80% of the total incidence of clinical stroke. High morbidity, disability, and mortality rates place heavy burdens on the families of patients and society. An increasing number of studies have shown that histone modification plays an important role in the pathogenesis of ischemic stroke, but most studies on histone modification focus on acetylation, and studies on the role of histone methylation in the pathogenesis of ischemic stroke are limited. Here, we review the role of histone methylation and related histone methyltransferase (HMT) inhibitors in the pathogenesis of ischemic stroke and related HMT inhibitors in the treatment of ischemic stroke, which may open up a new avenue to the study of ischemic stroke. (AU)

Exendin-4 may improve type 2 diabetes by modulating the epigenetic modifications of pancreatic histone H3 in STZ-induced diabetic C57BL/6 J mice

Type 2 diabetes (T2D) is a complicated systemic disease that might be improved by exendin-4, although the epigenetic role remains unclear. In the current study, C57BL/6 J mice were used to generate a T2D model, followed by treatment with exendin-4 (10 μg/kg). Histone H3K9 and H3K23 acetylation, H3K4 mono-methylation, and H3K9 di-methylation were explored by western blot analysis of pancreatic histone extracts. Real-time polymerase chain reaction (PCR) was used to examine the expression levels of pancreatic beta cell development-related genes, and chromatin immunoprecipitation (ChIP) was applied to analyze H3 and H3K9 acetylation, H3K4 mono-methylation, and H3K9 di-methylation in the promoter region of the pancreatic and duodenal homeobox 1 (Pdx1) gene. The results showed that total H3K9 di-methylation and H3K9 and H3K23 acetylation increased in pancreatic tissues of diabetic mice, whereas H3K4 mono-methylation was reduced. All of these changes could be abrogated by treatment with exendin-4. Our data indicated that T2D progression might be improved by exendin-4 treatment through the reversal of global pancreatic histone H3K9 and H3K23 acetylation, H3K4 mono-methylation, and H3K9 di-methylation. A better understanding of these epigenetic alterations may, therefore, lead to novel therapeutic strategies for T2D. (AU)

Circular RNA hsa_circ_0091579 facilitates the Warburg effect and malignancy of hepatocellular carcinoma cells via the miR-624/H3F3B axis

Background Hepatocellular carcinoma (HCC) is a primary liver cancer with a high mortality rate. It has been reported that circular RNA hsa_circ_0091579 (circ_0091579) is involved in HCC progression. Nevertheless, the molecular mechanism by which circ_0091579 modulates HCC advancement is indistinct.MethodsThe expression of circ_0091579, microRNA (miR)-624, and H3 histone family member 3B (H3F3B) mRNA was evaluated by quantitative real-time polymerase chain reaction (qRT-PCR). The extracellular acidification rate (ECAR) and oxygen consumption rate (OCR) of HCC cells were analyzed using an extracellular flux analyzer. Adenosine triphosphate (ATP) level was evaluated using a commercial kit. Cell migration, invasion, and apoptosis were assessed by wound-healing, transwell, or flow cytometry assay. The relationship between miR-624 and circ_0091579 or H3F3B was verified using luciferase reporter assay and/or RNA immunoprecipitation (RIP) assay. H3F3B protein level was detected by western blotting.ResultsCirc_0091579 was upregulated in HCC tissues and cells. Circ_0091579 inhibition decreased xenograft tumor growth in vivo and repressed Warburg effect, migration, invasion, and induced apoptosis of HCC cells in vitro. MiR-624 was downregulated, while H3F3B was upregulated in HCC tissues and cells. Circ_0091579 acted as a miR-624 sponge and regulated H3F3B expression by adsorbing miR-624. MiR-624 inhibitor reversed circ_0091579 downregulation-mediated effects on the Warburg effect and malignant behaviors of HCC cells. H3F3B overexpression reversed the repressive impact of miR-624 mimic on the Warburg effect and malignancy of HCC cells.ConclusionsCirc_0091579 accelerated Warburg effect and tumor growth via upregulating H3F3B via adsorbing miR-624 in HCC, providing evidence to support the involvement of circ_0091579 in the progression of HCC. (AU)

Modificaciones epigenéticas en las cefaleas / Epigenetic changes in headache

Introducción: En las cefaleas parece existir una influencia multifactorial, tanto de mecanismos genéticos como ambientales, siendo interesante el estudio de la posible participación de mecanismos epigenéticos en su desarrollo, cronificación y potencial papel como diana terapéutica.MétodosHemos llevado a cabo una revisión bibliográfica, principalmente a través de la base de datos Medline/PubMed, de la implicación de los distintos mecanismos epigenéticos en las cefaleas. Para ello hemos utilizado los términos de búsqueda en inglés: headache, migraine, epigenetics, DNA methylation, histones, non-coding RNA y miRNA.ResultadosSe obtuvieron un total de 15 publicaciones en idioma inglés relacionadas con los términos anteriores.ConclusionesExisten indicios de la relación entre la epigenética y las cefaleas, siendo imprescindible, debido al reducido número de estudios, continuar con la investigación de las modificaciones epigenéticas en las cefaleas. Esto podría ayudar a comprender la fisiopatología de las cefaleas e incluso identificar biomarcadores y nuevas dianas terapéuticas más eficaces. (AU)

Introduction: Multiple factors, including both genetic and environmental mechanisms, appear to play a role in the aetiology of headache. An interesting area of study is the possible involvement of epigenetic mechanisms in headache development and the transformation to chronic headache, and the potential role of these factors as a therapeutic target.MethodsWe performed a literature review of the involvement of different epigenetic mechanisms in headache, mainly using the Medline/PubMed database. To this end, we used the following English search terms: headache, migraine, epigenetics, DNA methylation, histones, non-coding RNA, and miRNA.ResultsA total of 15 English-language publications related to the above terms were obtained.ConclusionThere is limited but consistent evidence of the relationship between epigenetics and headache; it is therefore essential to continue research of epigenetic changes in headache. This may help to understand the pathophysiology of headache and even to identify candidate biomarkers and new, more effective, therapeutic targets. (AU)

Neutrófilos como instigadores de trombosis: más allá de la protección antimicrobiana / Neutrophils as instigators of thrombosis: beyond antimicrobial protection

Los neutrófilos, cuando son activados, liberan estructuras (NETs) compuestas por ADN, histonas y proteínas granulares que proporcionan una matriz idónea para la activación plaquetaria y de los mecanismos de coagulación, contribuyendo así a la patogenia de la trombosis en los territorios venoso y arterial, así como a la trombosis asociada a cáncer. Los NETs desempeñan un papel clave en la inmunotrombosis, término que describe la relación entre la respuesta inmune y la coagulación

When activated, neutrophils release structures (NETs) composed of DNA, histones and granular proteins that provide an ideal matrix for platelet activation and coagulation mechanisms, thereby contributing to the pathogenesis of thrombosis in venous and arterial territories, as well as cancer-associated thrombosis. NETs play a key role in immunothrombosis, a term that describes the relationship between the immune response and coagulation

Talleres de Autoinmunidad: Anticuerpos antinucleosomas y otras especificidades nucleares / No disponible

No disponible

La epigenética en el tratamiento del dolor / Epigenetics in the treatment of pain

Introducción: La epigenética se refiere a los cambios en el ADN e histonas que no implican alteraciones en la secuencia de nucleótidos y modifican la estructura y condensación de la cromatina, afectando de esta manera la expresión génica y el fenotipo. Las modificaciones epigenéticas son metilación del ADN y modificaciones de histonas. Objetivo: Realizar una revisión de la literatura sobre la importancia de la epigenética en la fisiopatología y el tratamiento del dolor. Materiales y métodos: se hizo una revisión de la bibliografía sobre el concepto de epigenética, sus bases biológicas, impacto sobre el dolor y su relación con posibles tratamientos. Resultados: Los mecanismos epigenéticos han cobrado cada vez más importancia debido a la creciente asociación con enfermedades complejas y comunes, así como por su influencia en el dolor y sus posibles tratamientos. Conclusiones: La epigenética tiene una clara relación en el dolor, en sus bases fisiopatológicas y posibles tratamientos

Introduction: Epigenetics refers to changes in DNA and histones that do not involve alterations in the nucleotide sequence and modify the structure and condensation of the chromatin, thus affecting gene expression and phenotype. Epigenetic modifications are DNA methylation and histone modifications. Objective: To carry out a review of the literature on the importance of Epigenetics in the pathophysiology and treatment of pain. Materials and methods: A review of the literature on the concept of epigenetics, its biological bases, the impact on pain and its relation to possible treatments. Results: Epigenetic mechanisms have become increasingly important due to the growing association with complex and common diseases, as well as their influence on pain and its possible treatments. Conclusions: Epigenetics has a clear relationship in pain, its pathophysiological bases and possible treatments

Epigenetic modulators of thyroid cancer / Moduladores epigenéticos del cancer de tiroides

There are some well known factors involved in the etiology of thyroid cancer, including iodine deficiency, radiation exposure at early ages, or some genetic changes. However, epigenetic modulators that may contribute to development of these tumors and be helpful to for both their diagnosis and treatment have recently been discovered. The currently known changes in DNA methylation, histone modifications, and non-coding RNAs in each type of thyroid carcinoma are reviewed here (AU)

Son conocidos algunos factores implicados en la etiología del cáncer de tiroides como el déficit de yodo o la exposición a radiación en edades tempranas o algunas alteraciones genéticas. Sin embargo, en los últimos años se han descubierto moduladores epigenéticos que puedan contribuir al desarrollo de estos tumores y podrían tener una utilidad tanto en el diagnóstico como en el tratamiento. En esta revisión se repasan las alteraciones conocidas hasta ahora tanto en la metilación del ADN como en las modificaciones de las histonas y los ARN no codificantes en cada uno de los tipos de carcinomas de tiroides (AU)

Epigenética en la arteriosclerosis / Epigenetics in atherosclerosis

Los estudios de asociación basados en genes candidato llevados a cabo durante décadas han servido para visualizar la influencia del componente genético en enfermedades complejas como la arteriosclerosis y también para evidenciar la interacción entre diferentes genes y, especialmente, la de estos con factores ambientales. Incluso con el conocimiento acumulado, aún queda camino por recorrer para descifrar la predisposición individual a la enfermedad y, si tenemos en cuenta la gran influencia que los factores ambientales juegan en el desarrollo y la progresión de la arteriosclerosis, la epigenética se nos presenta como un elemento clave para ampliar nuestro conocimiento de la predisposición individual a la arteriosclerosis. La epigenética se puede describir como la disciplina que estudia los mecanismos de regulación transcripcional independientes de la secuencia del ADN, mayoritariamente inducidos por factores ambientales. Esta revisión pretende describir qué es la epigenética y de qué manera los mecanismos epigenéticos participan en la arteriosclerosis

The association studies based on candidate genes carried on for decades have helped in visualizing the influence of the genetic component in complex diseases such as atherosclerosis, also showing the interaction between different genes and environmental factors. Even with all the knowledge accumulated, there is still some way to go to decipher the individual predisposition to disease, and if we consider the great influence that environmental factors play in the development and progression of atherosclerosis, epigenetics is presented as a key element in trying to expand our knowledge on individual predisposition to atherosclerosis and cardiovascular disease. Epigenetics can be described as the discipline that studies the mechanisms of transcriptional regulation, independent of changes in the sequence of DNA, and mostly induced by environmental factors. This review aims to describe what epigenetics is and how epigenetic mechanisms are involved in atherosclerosis

Nutrición y Epigenética en Pediatría / Nutrition and Epigenetics in Pediatrics

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Epigenética y epilepsia / Epigenetics and epilepsy

Introducción: La epigenética es el estudio de los cambios heredables en el ADN sin afectar a las secuencia de nucleótidos. Entre los mecanismos de regulación epigenética, los más estudiados y conocidos hasta la fecha son la metilación del ADN, la modificación de las histonas y los ARN no codificantes. Mediante estos mecanismos se regula la expresividad génica y la alteración de los mismos puede llevar al desarrollo de patologías. Desarrollo: Describimos los principales mecanismos de regulación epigenética y realizamos una revisión de la bibliografía reciente sobre los mecanismos de regulación epigenética y su implicación en distintos síndromes epilépticos. Conclusión: La identificación de los mecanismos epigenéticos implicados en la epilepsia constituye una prometedora vía de investigación para profundizar en el conocimiento de la fisiopatología y terapéutica de esta enfermedad

Introduction: Epigenetics is the study of heritable modifications in gene expression that do not change the DNA nucleotide sequence. Some of the most thoroughly studied epigenetic mechanisms at present are DNA methylation, post-transcriptional modifications of histones, and the effect of non-coding RNA molecules. Gene expression is regulated by means of these mechanisms and disruption of these molecular pathways may elicit development of diseases. Development: We describe the main epigenetic regulatory mechanisms and review the most recent literature about epigenetic mechanisms and how those mechanisms are involved in different epileptic syndromes. Conclusion: Identifying the epigenetic mechanisms involved in epilepsy is a promising line of research that will deliver more in-depth knowledge of epilepsy pathophysiology and treatments

Liver histone H3 methylation and acetylation may associate with type 2 diabetes development

Type 2 diabetes (T2D) is a complicated systemic disease, and the exact pathogenetic molecular mechanism is unclear. Distinct histone modifications regulate gene expression in certain diseases, but little is known about histone epigenetics in diabetes. In the current study, C57BL/6 J mice were used to build T2D model, then treated with exendin-4 (10 μg/kg). Histone H3K9 and H3K23 acetylation, H3K4 monomethylation and H3K9 dimethylation were explored by Western blotting of liver histone extracts. Real-time polymerase chain reaction (PCR) was used to examine expression levels of diabetes-related genes, while chromatin immunoprecipitation (ChIP) was applied to analyze H3 and H3K9 acetylation, H3K4 monomethylation, and H3K9 dimethylation in the promoter of facilitated glucose transporter member 2 (Glut2) gene. The results showed that liver’s total H3K4 monomethylation and H3K9 dimethylation was increased in diabetic mice, which was abrogated with the treatment of exendin-4. In contrast, H3K9 and H3K23 acetylation were reduced in diabetic mice, while exendin-4 only alleviated the reduction of H3K9 acetylation. Our data indicated that the progression of type 2 diabetes mellitus (T2D) is associated with global liver histone H3K9 and H3K23 acetylation, H3K4 monomethylation, and H3K9 dimethylation. Exploiting exact histone modify enzyme inhibitors, which may represent a novel strategy to prevent T2D

Biomarcadores en cáncer. Contribución de la epigenética a la medicina personalizada / Biomarkers in cancer. contribution of epigenetics in personalised medicine

En el contexto de la medicina personalizada, la epigenética cobra importancia como base de prevención, diagnóstico, prognosis y tratamiento de enfermedades como el cáncer. De los distintos procesos de control epigenético, el silenciamiento génico por metilación del ADN es el más frecuente en esta patología y aporta aplicaciones clínicas muy variadas como predicción de respuesta terapéutica, prognosis asociada a las características moleculares del tumor y el seguimiento de pacientes tras la intervención quirúrgica o el tratamiento con quimioterapia. Una de las principales ventajas clínicas de estas alteraciones epigenéticas es que pueden revertirse mediante tratamientos farmacológicos, aunque se asocien con múltiples efectos secundarios. Es por ello de gran importancia continuar con el estudio de la regulación epigenética en cáncer, complementado con la biología de sistemas, lo que aportaría conocimiento sobre la implicación biológica real de estos biomarcadores, y la identificación de fármacos específicos que disminuyan estos efectos adversos y nos acerquen a la realidad de una medicina personalizada (AU)

In the context of personalised medicine, epigenetics has an important role as regards he prevention, diagnosis, prognosis, and treatment of diseases such as cancer. Of the different epigenetic control processes, gene silencing by DNA methylation is most frequent in this disease, and contributes to a wide variety of clinical applications such as, prediction of the therapeutic response, the prognosis associated with the molecular characteristics of the tumour, and the follow-up pf patients after treatment by surgery or chemotherapy. One of the main advantages of these epigenetic alterations is that they can be reversed with pharmacological treatments, although they are associated with multiple side effects. It for this reason, it is of great importance to continue studying epigenetic regulation in cancer, complementing with biological systems, as well as the identification of specific drugs that may decrease these adverse effects, and which should help to determine the real biological implications of these biomarkers and may lead to achieving personalised medicine (AU)

Epigenética y cáncer colorrectal / Epigenetics and colorectal cancer

Los mecanismos epigenéticos fisiológicos que pueden modificar la estructura de la cromatina comprenden la metilación del ADN, las modificaciones de las histonas y las modificaciones en el RNA. Se ha llevado a cabo una revisión bibliográfica en PubMed acerca de la evidencia publicada sobre la relación existente entre la epigenética y el cáncer colorrectal. La literatura científica pone de manifiesto que en el origen de la enfermedad neoplásica las alteraciones epigenéticas pueden ser tan importantes como las modificaciones genéticas, contribuyendo ambas a la progresión y desarrollo de la enfermedad neoplásica (AU)

The epigenetic and physiological mechanisms that alter the structure of chromatin include the methylation of DNA, changes in the histones, and changes in RNA. A literature review has been carried out using PubMed on the evidence published on the association between epigenetics and colorectal cancer. The scientific literature shows that epigenetic changes, such as genetic modifications may be very significant in the origin of neoplastic disease, contributing both to the development and progression of the disease (AU)