Distribution of 5-methylcytosine and 5-hydroxymethylcytosine in bovine fetal tissue of the placenta / Distribuição de 5-metilcitosina e 5-hidroximetilcitosina em placenta fetal bovina

5-methylcytosine (5-mC) and 5-hydroxymethylcytosine (5-hmC) are modified cytosines found in mammals that are involved in the regulation of gene expression. The aim of this study was to characterize the global patterns of 5-mC and 5-hmC of the fetal placenta of Nellore cattle as well as blood and sperm as controls. 5-mC and 5-hmC levels were determined using MethylFlash Methylated/Hydroxymethylated DNA Quantification Kit, respectively. Placenta tissues showed lower levels of 5-mC and 5-hmC compared to sperm. The male cotyledon showed higher levels of 5-hmC than the female. For the first time, the levels of 5-mC and 5-hmC in Bos taurus indicus were characterized, which may contribute to our understanding of the mechanisms of epigenetic regulation in the placenta. The presence of 5-hmC in somatic tissues suggest that 5-hmC has its own biological function and it is not only a byproduct from the oxidation of 5-mC. These results may be of interest in ARTs, especially in cloning in the diagnosis/prognosis of aberrant placentation and the viability of pregnancies.(AU)

5-metilcitosina (5-mC) e 5-hidroximetilcitosina (5-hmC) são citosinas modificadas encontradas nos mamíferos que estão envolvidas com a regulação da expressão gênica. O objetivo do presente estudo foi caracterizar os padrões globais de 5-mC e 5-hmC em placenta fetal de animais da raça Nelore, assim como em sangue e espermatozoides, usados como controles. Os níveis de 5-mC e 5-hmC foram determinados usando os kits MethylFlash Methylated/Hydroxymethylated DNA Quantification, respectivamente. Tecidos placentários apresentaram menores níveis de 5-mC e 5-hmC quando comparados com espermatozoides. Cotilédones de machos apresentaram maiores níveis de 5-hmC do que os de fêmeas. Os níveis de 5-mC e 5-hmC em animais Bos taurus indicus foram caracterizados pela primeira vez, o que pode contribuir para o nosso conhecimento sobre a regulação dos mecanimos epigenéticos na placenta. A presença de 5-hmC em tecidos somáticos sugerem que essa base pode ter sua própria função biológica, sendo não somente um sub-produto da oxidação da 5-mC. Esses resultados podem ser de interesse nas Tecnologias de Reprodução Assistida, especialmente na clonagem, no diagnóstico/prognóstico de placentação aberrante e viabilidade da progênie.(AU)

A Nexus model of cellular transition in cancer

The exact cause of cancer is one of the most immutable medical questions of the century. Cancer as an evolutionary disease must have a purpose and understanding the purpose is more important than decoding the cause. The model of cancer proposed herein, provides a link between the cellular biochemistry and cellular genetics of cancer evolution. We thus call this model as the "Nexus model" of cancer. The Nexus model is an effort to identify the most apparent route to the disease. We have tried to utilize existing cancer literature to identify the most plausible causes of cellular transition in cancer, where the primary cancer-causing agents (physical, chemical or biological) act as inducing factors to produce cellular impeders. These cellular impeders are further linked to the Nexus. The Nexus then generates codes for epigenetics and genetics in cancer development.

Schizophrenia and reelin: a model based on prenatal stress to study epigenetics, brain development and behavior

Schizophrenia is a severe psychiatric disorder that results in a significant disability for the patient. The disorder is characterized by impairment of the adaptive orchestration of actions, a cognitive function that is mainly dependent on the prefrontal cortex. This behavioral deficit, together with cellular and neurophysiological alterations in the prefrontal cortex, as well as reduced density of GABAergic cells and aberrant oscillatory activity, all indicate structural and functional deficits of the prefrontal cortex in schizophrenia. Among the several risk factors for the development of schizophrenia, stress during the prenatal period has been identified as crucial. Thus, it is proposed that prenatal stress induces neurodevelopmental alterations in the prefrontal cortex that are expressed as cognitive impairment observed in schizophrenia. However, the precise mechanisms that link prenatal stress with the impairment of prefrontal cortex function is largely unknown. Reelin is an extracellular matrix protein involved in the development of cortical neural connectivity at embryonic stages, and in synaptic plasticity at postnatal stages. Interestingly, down-regulation of reelin expression has been associated with epigenetic changes in the reelin gene of the prefrontal cortex of schizophrenic patients. We recently showed that, similar to schizophrenic patients, prenatal stress induces down-expression of reelin associated with the methylation of its promoter in the rodent prefrontal cortex. These alterations were paralleled with altered prefrontal cortex functional connectivity and impairment in prefrontal cortex-dependent behavioral tasks. Therefore, considering molecular, cellular, physiological and behavioral evidence, we propose a unifying framework that links prenatal stress and prefrontal malfunction through epigenetic alterations of the reelin gene.

Nutritional aspects related to endometriosis / Aspectos nutricionais relacionados à endometriose

SUMMARY This literature review analyzed the evidence on nutritional aspects related to the pathogenesis and progression of endometriosis. Diets deficient in nutrients result in changes in lipid metabolism, oxidative stress and promote epigenetic abnormalities, that may be involved in the genesis and progression of the disease. Foods rich in omega 3 with anti-inflammatory effects, supplementation with Nacetylcysteine, vitamin D and resveratrol, in addition to the increased consumption of fruits, vegetables (preferably organic) and whole grains exert a protective effect, reducing the risk of development and possible regression of disease. Dietary re-education seems to be a promising tool in the prevention and treatment of endometriosis.

RESUMO Esta revisão de literatura analisou as evidências sobre aspectos nutricionais relacionados com a etiopatogenia e a progressão da endometriose. Dietas deficientes em nutrientes refletem-se em alterações no metabolismo lipídico, estresse oxidativo e favorecem anormalidades epigenéticas que podem estar envolvidas na gênese e na progressão da doença. Alimentos ricos em ômega-3, com efeito anti-inflamatório, suplementação com N-acetilcisteína, vitamina D e resveratrol, além do maior consumo de frutas, verduras (preferencialmente orgânicas) e cereais integrais, exercem efeito protetor, com redução no risco de desenvolvimento e possível regressão da doença. A reeducação alimentar parece ser uma ferramenta promissora na prevenção e no tratamento da endometriose.

Effect of dietary phytoestrogens on human growth regulation: imprinting in health & disease.

This group has advocated a return to the notional Palæolithic diet with fruits, vegetables, roots, leaves, seeds, phytochemical antioxidants and proteins, etc. Phytoestrogens, viz. lignans, isoflavonoids and flavonoids are weak oestrogenic constituents of such a diet and may have a considerable impact on human health and disease. The aim of this paper was to conduct a preliminary overview of about 2000 research-led studies from the 1930s to the present time reported in the literature on flavonoids/isoflavonoids/lignans and to assemble evidence for a future strictly formal literature review on the health benefits and risks of flavonoids in a variety of diseases.

Barrett's Esophagus and Cancer Risk: How Research Advances Can Impact Clinical Practice

Barrett's esophagus (BE) is the only known precursor to esophageal adenocarcinoma (EAC), whose incidence has increased sharply in the last 4 decades. The annual conversion rate of BE to cancer is significant, but small. The identification of patients at a higher risk of cancer therefore poses a clinical conundrum. Currently, endoscopic surveillance is recommended in BE patients, with the aim of diagnosing either dysplasia or cancer at early stages, both of which are curable with minimally invasive endoscopic techniques. There is a large variation in clinical practice for endoscopic surveillance, and dysplasia as a marker of increased risk is affected by sampling error and high interobserver variability. Screening programs have not yet been formally accepted, mainly due to the economic burden that would be generated by upper gastrointestinal endoscopy. Screening programs have not yet been formally accepted, mainly due to the economic burden that would be generated by widespread indication to upper gastrointestinal endoscopy. In fact, it is currently difficult to formulate an accurate algorithm to confidently target the population at risk, based on the known clinical risk factors for BE and EAC. This review will focus on the clinical and molecular factors that are involved in the development of BE and its conversion to cancer and on how increased knowledge in these areas can improve the clinical management of the disease.

Autismo y epigenética. Un modelo de explicación para la comprensión de la génesis en los trastornos del espectro autista / [Autism and epigenetics. A model of explanation for the understanding of the genesis in autism spectrum disorders].

Autism spectrum disorders are characterized by impairment of social integration and language development and restricted interests. Autism spectrum disorders manifest during childhood and may have a varying clinical expression over the years related to different therapeutic approaches, behavior-modifying drugs, and environmental factors, among others. So far, the genetic alterations identified are not sufficient to explain the genesis of all these processes, as many of the mutations found are also present in unaffected individuals. Findings on the underlying biological and pathophysiological mechanisms of entities strongly associated with autism spectrum disorders, such as Rett, fragile X, Angelman, and fetal alcohol syndromes, point to the role of epigenetic changes in disorders of neurodevelopment. Epigenetic phenomena are normal biological processes necessary for cell and thus human life, especially related to embryonic development. Different phenomena that affect epigenetic processes (changes that change operation or expression of a gene, without modifying the DNA structure) have also been shown to be important in the genesis of neurodevelopmental disorders. Alterations in the epigenetic mechanism may be reversible, which may explain the variation in the autism phenotype over time. Here we analyze the normal epigenetic mechanisms, autism spectrum disorders, their association with specific entities associated with altered epigenetic mechanisms, and possible therapeutic approaches targeting these alterations.

Perfil de metilación de genes supresores de tumores como factor pronóstico en pacientes con leucemia mieloide aguda / Promoter methylation profile in tumor suppressor genes as prognosis factor in patients with acute myeloid leukemia

Existe creciente evidencia que apoya la presencia de un perfil de metilación específico para Leucemia Mieloide Aguda (LMA). La metilación de los islotes CpG en las regiones promotoras de los genes supresores de tumores es un importante mecanismo de control epigenético y participa en el silenciamiento transcripcional. Esto puede contribuir a un nuevo entendimiento de la biología de la enfermedad y vislumbrar nuevas oportunidades terapéuticas. Identificar el perfil de metilación de las áreas promotoras de un grupo de genes supresores de tumores; (p15, p16, ESR1, IGSF4, SOCS1, RARB y DAPK), y relacionar el estatus de metilación gen especifica o combinada con diferentes parámetros clínico patológicos. Se utilizaron muestras de sangre o médula ósea obtenidas al momento del diagnóstico de 33 pacientes con LMA, infantil y del adulto, recolectadas entre los años 1997 y 2008 en el Hospital Hernán Henríquez de Temuco. Se evaluó la presencia de hipermetilación mediante una Reacción de Polimerasa en Cadena Metilación Específica (MSP), previa modificación con bisulfito de sodio. La frecuencia de metilación de los pacientes estudiados fue de 88 por ciento, 27 por ciento, 27 por ciento, 21 por ciento, 15 por ciento, 3 por ciento y 0 por ciento para ESR1, RARb, IGSF4, p15, SOCS1, DAPK, y P16, respectivamente. La hipermetilación de P15 y RARb presentó una asociación significativa para una menor supervivencia en forma individual (p=0,03 y p=0,02), y combinada (p=0,002). No se encontraron diferencias significativas entre metilación y los otros parámetros clínicos analizados. Los pacientes con LMA presentan hipermetilación de la región promotora en algunos genes supresores de tumores, afectando negativamente la supervivencia. Esto pudiese eventualmente contribuir al establecimiento de un patrón de metilación determinado con utilidad clínica.

There is growing evidence than acute myeloid leukemia presents a specific methylation profile. The Methylation of CpG islands within gene promoters is a major epigenetic transcriptional control mechanism and plays a critical role in the transcriptional silencing of tumor suppressor genes. This provides new insights into the biology of the disease and it may offer novel therapeutic opportunities. To identify the promoter methylation profile of tumor suppressor genes (p15, p16, ESR1, IGSF4, SOCS1, RARB y DAPK), and to relate the percentage of methylation with clinicopathological features, as age, gender, white cell count, disease classification and survival rates. Bone marrow and peripheral blood samples were collected at diagnosis from 33 patients with acute myeloid leukemia, infants and adult, between 1997 and 2008 from Hernán Henríquez Aravena Hospital, Temuco, Chile. Methylation in the promoter areas of each tumor suppressor gene was analyzed using the mehylation specific polymerase chain reaction (MSP) technique using sodium bisulfite modification. The frequency of hypermethylation among the patient samples was 88 percent, 27 percent, 27 percent, 21 percent, 15 percent, 3 percent and 0 percent for ESR1, RARb, IGSF4, p15, SOCS1, DAPK, and P16 for each one. Methylation was significantly associated with an inferior overall survival (p=0.03 and p=0.02). When both genes are used, inferior survival is even more significant (p=0.002). There is no significant correlation between methylation and clinicopathological features.Patients with AML have hipermetilation at the promoter region of some tumor supressor genes, with a negative effect in the overall survival. This could eventually become part of establishing a characteristical methilation pattern with clinical utility.

The central role of RNA in the genetic programming of complex organisms

Notwithstanding lineage-specific variations, the number and type of protein-coding genes remain relatively static across the animal kingdom. By contrast there has been a massive expansion in the extent of genomic non-proteincoding sequences with increasing developmental complexity. These non-coding sequences are, in fact, transcribed in a regulated manner to produce large numbers of large and small non-protein-coding RNAs that control gene expression at many levels including chromatin architecture, post-transcriptional processing and translation. Moreover, many RNAs are edited, especially in the nervous system, which may be the basis of epigenome-environment interactions and the function of the brain.

Apesar das variações linhagem-específicas, o número e tipo de genes codificadores de proteínas permanecem relativamente estáticos no reino animal. Em contraste, houve uma expansão maciça da quantidade de sequências genômicas não-codificadoras de proteínas com o aumento da complexidade do desenvolvimento. Essas sequências não codificadoras são, de fato, transcritas de maneira regulada para produzirem numerosos RNAs grandes e pequenos não-codificadores de proteínas que controlam a expressão de genes em vários níveis, incluindo a arquitetura da cromatina, o processamento pós-transcricional e a tradução. Além disso, muitos RNAs são editados, especialmente no sistema nervoso, o que pode ser a base de interações epigenoma-ambiente e a função do cérebro.

Metilación y expresión de genes en el cáncer diferenciado de tiroides / Methylation and expression of genes in thyroid differentiated cancer

En los últimos años ha cobrado importancia el estudio de las alteraciones epigenéticas en el desarrollo del cáncer. La metilación del ácido desoxirribonucleico es el cambio epigenético más frecuente e importante hasta ahora estudiado, y tiene un importante papel en la regulación transcripcional de genes. Recientemente se ha observado que existen patrones de metilación anormales en muchos tipos de cánceres, incluyendo el cáncer de tiroides, los cuales conducen a la inactivación de genes supresores de tumores y a la inestabilidad del genoma. La metilación de genes específicos, tales como, el cotransportador de yodo/sodio, la tiroglobulina y el receptor de la hormona estimulante del tiroides en el cáncer diferenciado de tiroides, es una de las causas de fallo en el tratamiento de los pacientes con esta enfermedad. Se ha iniciado el tratamiento con agentes desmetilantes en los pacientes con cáncer de tiroides que presentan una alteración genética por metilación, a fin de corregir estas alteraciones, restablecer la función, y con ello, la posibilidad de que el tratamiento sea efectivo(AU)

In past years the study of epigenetic alterations in the cancer development becomes significance. The methylation of desoxyribonucleic acid is the more frequent and important epigenetic change until now studied and play a significant role in the transcription regulation of genes. Recently it was noted the existence of abnormal methylation patterns in many types of cancer, including the thyroid one, which leading to inactivation of tumor suppressors genes and to genome instability. The methylation of specific genes such as the co-transporter of iodine/sodium, the thyroglobulin and the receptor of thyroid stimulant hormone (TSH) in the thyroid differentiated cancer, is one of the failure cause in treatment of patients presenting this disease. In patients with thyroid cancer it has been initiated a treatment with demethylation agents in patients with abovementioned cancer with a genetic alteration due to methylation to correct these alterations, to restore the function and thus the possibility of a effective treatment(AU)

Aportes de la epigenética en la comprensión del desarrollo del ser humano: [revisión] / Contribution of epigenetics to understand human development: [review]

Epigenetics refers to the study of how genes produce their effect on the phenotype of the organism. This article is a review on the scope and importance of recently discovered epigenetic mechanisms on human development and their relationship to perinatal epidemiological issues. It shows a general view and present concepts about epigenetics and its contribution to the comprehension of several physiologic and pathological conditions of human beings. Secondly, it analyzes the evidence coming from epidemiological and animal studies, about the influence of events that occur in the perinatal and early postnatal periods on adult life and the possible epigenetic mechanisms involved. Lastly, it underscores the implications ofthese results of future research and the design of public policies that take into account the importance of events in early life in thefuture development of individuals.

Epigenetic Cross-Talk between DNA Methylation and Histone Modifications in Human Cancers

DNA methylation, histone modifications, and the chromatin structure are profoundly altered in human cancers. The silencing of cancer-related genes by these epigenetic regulators is recognized as a key mechanism in tumor formation. Recent findings revealed that DNA methylation and histone modifications appear to be linked to each other. However, it is not clearly understood how the formation of histone modifications may affect DNA methylation and which genes are relevantly involved with tumor formation. The presence of histone modifications does not always link to DNA methylation in human cancers, which suggests that another factor is required to connect these two epigenetic mechanisms. In this review, examples of studies that demonstrated the relationship between histone modifications and DNA methylation in human cancers are presented and the potential implications of these epigenetic mechanisms in human neoplasia are discussed.

Epigenetic Cross-Talk between DNA Methylation and Histone Modifications in Human Cancers

DNA methylation, histone modifications, and the chromatin structure are profoundly altered in human cancers. The silencing of cancer-related genes by these epigenetic regulators is recognized as a key mechanism in tumor formation. Recent findings revealed that DNA methylation and histone modifications appear to be linked to each other. However, it is not clearly understood how the formation of histone modifications may affect DNA methylation and which genes are relevantly involved with tumor formation. The presence of histone modifications does not always link to DNA methylation in human cancers, which suggests that another factor is required to connect these two epigenetic mechanisms. In this review, examples of studies that demonstrated the relationship between histone modifications and DNA methylation in human cancers are presented and the potential implications of these epigenetic mechanisms in human neoplasia are discussed.

Roles and causes of abnormal DNA methylation in gastrointestinal cancers.

Evidence now suggests that epigenetic abnormalities, particularly altered DNA methylation, play a crucial role in the development and progression of human gastrointestinal malignancies. Two distinct DNA methylation abnormalities are observed together in cancer. One is an overall genome-wide reduction in DNA methylation (global hypomethylation) and the other is regional hypermethylation within the CpG islands of specific gene promoters. Global hypomethylation is believed to induce proto-oncogene activation and chromosomal instability, whereas regional hypermethylation is strongly associated with transcriptional silencing of tumor suppressor genes. To date, genes involved in regulation of the cell cycle, DNA repair, growth signaling, angiogenesis, and apoptosis, are all known to be inactivated by hypermethylation. Recently developed techniques for detecting changes in DNA methylation have dramatically enhanced our understanding of the patterns of methylation that occur as cancers progress. One of the key contributors to aberrant methylation is aging, but other patterns of methylation are cancer-specific and detected only in a subset of tumors exhibiting the CpG island methylator phenotype (CIMP). Although the cause of altered patterns of DNA methylation in cancer remains unknown, it is believed that epidemiological factors, notably dietary folate intake, might strongly influence DNA methylation patterns. Recent studies further suggest that polymorphisms of genes involved in folate metabolism are causally related to the development of cancer. Identifying epidemiological factors responsible for epigenetic changes should provide clues for cancer prevention in the future.

The prima donna of epigenetics: the regulation of gene expression by DNA methylation

This review focuses on the mechanisms of DNA methylation, DNA methylation pattern formation and their involvement in gene regulation. Association of DNA methylation with imprinting, embryonic development and human diseases is discussed. Furthermore, besides considering changes in DNA methylation as mechanisms of disease, the role of epigenetics in general and DNA methylation in particular in transgenerational carcinogenesis, in memory formation and behavior establishment are brought about as mechanisms based on the cellular memory of gene expression patterns.