Epigenetic changes in neurology: DNA methylation in multiple sclerosis. / Modificaciones epigenéticas en neurología: alteraciones en la metilación del ADN en la esclerosis múltiple.

INTRODUCTION: Epigenetics is defined as the study of the mechanisms that regulate gene expression without altering the underlying DNA sequence. The best known is DNA methylation. Multiple Sclerosis (MS) is a disease with no entirely known etiology, in which it is stated that the involvement of environmental factors on people with a genetic predisposition, may be key to the development of the disease. It is at this intersection between genetic predisposition and environmental factors where DNA methylation may play a pathogenic role. DEVELOPMENT: A literature review of the effects of environmental risk factors for the development of MS can have on the different epigenetic mechanisms as well as the implication that such changes have on the development of the disease. CONCLUSION: Knowledge of epigenetic modifications involved in the pathogenesis of MS, opens a new avenue of research for identification of potential biomarkers, as well as finding new therapeutic targets.

Clinical, molecular, and pharmacological aspects of FMR1 related disorders. / Aspectos clínicos, moleculares y farmacológicos en los trastornos asociados a gen 1 del retraso mental del X frágil.

BACKGROUND: Fragile X syndrome, the most common inherited cause of intellectual disability, is associated with a broad spectrum of disorders across different generations of a single family. This study reviews the clinical manifestations of fragile X-associated disorders as well as the spectrum of mutations of the fragile X mental retardation 1 gene (FMR1) and the neurobiology of the fragile X mental retardation protein (FMRP), and also provides an overview of the potential therapeutic targets and genetic counselling. DEVELOPMENT: This disorder is caused by expansion of the CGG repeat (>200 repeats) in the 5 prime untranslated region of FMR1, resulting in a deficit or absence of FMRP. FMRP is an RNA-binding protein that regulates the translation of several genes that are important in synaptic plasticity and dendritic maturation. It is believed that CGG repeat expansions in the premutation range (55 to 200 repeats) elicit an increase in mRNA levels of FMR1, which may cause neuronal toxicity. These changes manifest clinically as developmental problems such as autism and learning disabilities as well as neurodegenerative diseases including fragile X-associated tremor/ataxia syndrome (FXTAS). CONCLUSIONS: Advances in identifying the molecular basis of fragile X syndrome may help us understand the causes of neuropsychiatric disorders, and they will probably contribute to development of new and specific treatments.

[Infections and epigenetic changes in cancer]. / Infecciones y alteraciones epigenéticas en cáncer.

The role of epigenetics and infectious diseases at early stages of life influence pre-malignant lesions of cancer, in particular, gastric cancer, one of the most frequent tumours in Chile, Latin America, and worldwide. This article examines the role of H.pylori and epigenetic alterations (i.e. DNA methylation) at early stages of gastric cancer and proposes, from the paediatric point of view, strategies for prevention and early detection.

[Epigenetics and obesity]. / Epigenética y obesidad.

Current evidence supports the notion that exposure to various environmental conditions in early life may induce permanent changes in the epigenome that persist throughout the life-course. This article focuses on early changes associated with obesity in adult life. A review is presented on the factors that induce changes in whole genome (DNA) methylation in early life that are associated with adult onset obesity and related disorders. In contrast, reversal of epigenetic changes associated with weight loss in obese subjects has not been demonstrated. This contrasts with well-established associations found between obesity related DNA methylation patterns at birth and adult onset obesity and diabetes. Epigenetic markers may serve to screen indivuals at risk for obesity and assess the effects of interventions in early life that may delay or prevent obesity in early life. This might contribute to lower the obesity-related burden of death and disability at the population level. The available evidence indicates that epigenetic marks are in fact modifiable, based on modifications in the intrauterine environment and changes in food intake, physical activity and dietary patterns patterns during pregnancy and early years of adult life. This offers the opportunity to intervene before conception, during pregnancy, infancy, childhood, and also in later life. There must be documentation on the best preventive actions in terms of diet and physical activity that will modify or revert the adverse epigenetic markers, thus preventing obesity and diabetes in suceptible individuals and populations.

Childhood trauma is linked to epigenetic age deceleration in young adults with previous youth residential care placements.

Background: Early adversity increases the risk for mental and physical disorders as well as premature death. Epigenetic processes, and altered epigenetic aging in particular, might mediate these effects. While the literature that examined links between early adversity and epigenetic aging is growing, results have been heterogeneous.Objective: In the current work, we explored the link between early adversity and epigenetic aging in a sample of formerly out-of-home placed young adults.Method: A total of N = 117 young adults (32% women, age mean = 26.3 years, SD = 3.6 years) with previous youth residential care placements completed the Childhood Trauma Questionnaire (CTQ) and the Life Events Checklist (LEC-R) and provided blood samples for the analysis of DNA methylation using the Illumina Infinium MethylationEPIC BeadChip Microarray. Epigenetic age was estimated using Hovarth's and Hannum's epigenetic clocks. Furthermore, Hovarth's and Hannum's epigenetic age residuals were calculated as a proxy of epigenetic aging by regressing epigenetic age on chronological age. The statistical analysis plan was preregistered (https://osf.io/b9ev8).Results: Childhood trauma (CTQ) was negatively associated with Hannum's epigenetic age residuals, ß = -.23, p = .004 when controlling for sex, BMI, smoking status and proportional white blood cell type estimates. This association was driven by experiences of physical neglect, ß = -.25, p = .001. Lifetime trauma exposure (LEC-R) was not a significant predictor of epigenetic age residuals.Conclusion: Childhood trauma, and physical neglect in particular, was associated with decelerated epigenetic aging in our sample. More studies focusing on formerly institutionalized at-risk populations are needed to better understand which factors affect stress-related adaptations following traumatic experiences.

Growing literature links early adversity to altered epigenetic aging, yet results have been heterogeneous.We assessed childhood and lifetime trauma exposure using the Childhood Trauma Questionnaire and the Life Events Checklist and estimated epigenetic aging by obtaining Horvath's and Hannum's epigenetic age residuals in a sample of formerly out-of-home placed young adults.In this high-risk sample, childhood trauma, physical neglect in particular, but not lifetime trauma was negatively related to epigenetic aging.

Hepatocellular carcinoma in Peru: A molecular description of an unconventional clinical presentation.

INTRODUCTION AND AIM: Hepatocellular carcinoma (HCC) is the third most frequent cancer of digestive tract tumors in Peru, with a high mortality rate of 17.7 per 100,000 inhabitants. A significant number of HCC cases in Peru do not follow the classic clinical epidemiology of the disease described in other parts of the world. Those patients present with a distinct transcriptome profile and a singular tumor process, suggesting a particular type of hepatocarcinogenesis in a portion of the Peruvian population. Our aim was to understand the clinical and biologic involvement of the epigenetic profile (methylation) and gene expression (transcriptome) of HCC in Peruvian patients. METHODS: HCC and liver transcriptome and DNA methylation profiles were evaluated in 74 Peruvian patients. RESULTS: When grouped by age, there was greater DNA methylation in younger patients with HCC but no differences with respect to the transcriptomic profile. A high prevalence of the hepatitis B virus (HBV) (>90%) was also observed in the younger patients with HCC. Enrichment analyses in both molecular profiles pinpointed PRC2 as an important molecular effector of that liver tumor process in Peruvian patients. CONCLUSION: HCC in Peruvian patients has a unique molecular profile, associated with the presence of HBV, as well as overall DNA hypermethylation related to undifferentiated liver cells or cellular reprogramming.

No association between war-related trauma or PTSD symptom severity and epigenome-wide DNA methylation in Burundian refugees.

Background: War-related trauma is associated with varying posttraumatic stress disorder (PTSD) prevalence rates in refugees. In PTSD development, differential DNA methylation (DNAm) levels associated with trauma exposure might be involved in risk versus resilience processes. Studies investigating DNAm profiles related to trauma exposure and PTSD among refugees remain sparse.Objective: The present epigenome-wide association study investigated associations between war-related trauma, PTSD, and altered DNAm patterns in Burundian refugee families with 110 children and their 207 female and male caregivers.Method: War-related trauma load and PTSD symptom severity were assessed in structured clinical interviews with standardised instruments. Epigenome-wide DNAm levels were quantified from buccal epithelia using the Illumina EPIC beadchip.Results: Controlling for biological confounders, no significant epigenome-wide DNAm alterations associated with trauma exposure or PTSD were identified in children or caregivers (FDRs > .05). Co-methylated positions derived as modules from weighted gene correlation network analyses were not significantly associated with either war-related trauma experience in children or caregivers or with PTSD.Conclusions: These results do not provide evidence for altered DNAm patterns associated with exposure to war-related trauma or PTSD.

The study examines an understudied population in epigenome-wide association studies.Burundian refugees' war-trauma, PTSD, and DNA methylation were studied.Epigenome-wide DNA methylation was not significantly associated with war-trauma or PTSD in the conflict-affected sample.

Relationship between BsmI polymorphism and VDR gene methylation profile, gender, metabolic profile, oxidative stress, and inflammation in adolescents.

INTRODUCTION: Background: the biological activity of vitamin D depends on the activity of its receptor or VDR. On the other hand, the activity of this receptor is influenced by its state of methylation. The objective of this study was to verify if the BsmI polymorphism of the VDR gene influences its methylation profile in adolescents. Secondly, it was to verify if the status of some metabolic factors (oxidative stress, inflammation, lipid profile, and glycemia) in the serum, and gender-adjusted vitamin D levels are independent factors with an influence on the VDR methylation profile. Methods and results: the study included 198 adolescents of both sexes, aged 15-19 years, who underwent testing for VDR gene methylation polymorphisms, serum vitamin D levels, and metabolic, oxidative stress, and systemic inflammation markers. It was observed that the BB genotype was less methylated than the other groups (26.1 % versus 30.3 %, and 29.3 % for Bb and bb, respectively), although without statistical differences between them. The odds ratio indicated a protection of 13 % (partially methylated) for vitamin D status, while alpha glycols increased the risk ratio (of being partially methylated) by 3 %. MDA was protective at a 28 % chance of risk that adolescents with higher levels of lipid peroxidation would be hypomethylated. Conclusion: we conclude that the methylation profile of the VDR gene is not influenced by the different BsmI polymorphism genotypes, and that serum vitamin D and serum markers of oxidative stress and inflammation can modulate this profile.

INTRODUCCIÓN: Antecedentes: la actividad biológica de la vitamina D depende de la actividad de su receptor, el VDR. Por otro lado, la actividad de este receptor está influenciada por su estado de metilación. El objetivo de este estudio es verificar si el polimorfismo BsmI del gen VDR influye en el perfil de metilación del mismo en los adolescentes. En segundo lugar, verificar si los factores metabólicos (estrés oxidativo, inflamación, perfil lipídico y glucemia) del suero y la vitamina D ajustada por sexo actúan independientemente de los polimorfismos sobre el perfil de metilación del VDR. Métodos y resultados: el estudio incluyó a 198 adolescentes de ambos sexos, de 15 a 19 años de edad, que se sometieron a análisis de polimorfismos de metilación del gen VDR, niveles de vitamina D, marcadores metabólicos, estrés oxidativo e inflamación sistémica. Se observó que el genotipo BB estaba menos metilado que los otros grupos (26,1 % contra 30,3 % y 29,3 % para Bb y bb respectivamente), aunque sin diferencias estadísticas entre ellos. El odds ratio indicó una protección del 13 % (parcialmente metilado) para el estado de la vitamina D, mientras que los alfa glicoles aumentaron el índice de riesgo (de estar parcialmente metilado) en un 3 %. La MDA fue protectora con un 28 % de probabilidad de riesgo de que los adolescentes con niveles más altos de peroxidación lipídica fueran hipometilados. Conclusión: concluimos que el perfil de metilación del gen VDR no está influenciado por los diferentes genotipos del polimorfismo BsmI y que la vitamina D y los marcadores de estrés oxidativo e inflamación en el suero pueden modular este perfil.

Succinate dehydrogenase inhibitors fungicides: a review of their impact on human health and epigenetic changes / Fungicidas inibidores da succinato desidrogenase: uma revisao de seu impacto na saúde humana e alterares epigenéticas / Fungicidas inhibidores de la succinato deshidrogenasa: una revisión de su impacto en la salud humana y los cambios epigenéticos

Abstract Succinate dehydrogenase inhibitors (SDHIs), fungicides currently most used in agriculture in Brazil, act by blocking the enzyme succinate dehydrogenase (SDH) from plant pathogens. However, studies show that SDHIs can not only inhibit SDH activity in target fungi, but also block that activity in human cells. Considering the medical and agricultural implications of SDH, the purpose of this narrative review is to describe the relationship between exposure to fungicides SDHIs and epigenetic regulation of SDH associated with the development of gastrointestinal stromal tumor, pheochromocytoma/paraganglioma, and cancer. The results obtained with the research showed that the human SDH enzyme exhibited sensitivity to some tested SDHIs, which may cause microcephaly and defects in neurological development. Deficiency of SDH activity causes accumulation of succinate which can act as an oncometabolite inhibit-ing iron-dependent dioxygenases and alpha-ketoglutarate, eleven translocation -TET and histone demethylases, inducing epigenetic changes that lead to multiple cancers and other diseases. Therefore, further in vitro and in vivo analyzes should be performed to assess susceptibility to diseases influenced by the toxic effect of SDHIs.

Resumo Os inibidores da succinato desidrogenase (SDHIs), fungicidas atualmente mais utilizados na agricultura no Brasil, atuam bloqueando a enzima succinato desidrogenase (SDH) de fitopatógenos. No entanto, estudos mostram que SDHIs podem nao apenas inibir a atividade de SDH em fungos alvo, mas também bloquear essa atividade em células humanas. Considerando as implicares médicas e agrícolas do SDH, o objetivo desta revisao narrativa é descrever a relaqao entre a exposiqao a fungicidas SDHIs e a regulaqao epigenética do SDH associada ao desenvolvimento de tumor estromal gastrointestinal, feocromocitoma/paraganglioma e cáncer. Os resultados obtidos com a pesquisa mostraram que a enzima SDH humana apresentou sensibilidade a alguns SDHIs testados, que podem causar microcefalia e defeitos no desenvolvimento neurológico. A deficiencia da atividade da SDH causa acumulo de succinato que pode atuar como um oncometabólito inibindo as dioxigenases dependentes de ferro e alfa-cetoglutarato, onze translocaqóes -TET e histonas desmetilases, induzindo alteraqóes epigenéticas que levam a múltiplos canceres e outras doenqas. Portanto, análises adicionais in vitro e in vivo devem ser realizadas para avaliar a suscetibilidade a doenqas influenciadas pelo efeito tóxico dos SDHIs.

Resumen Los inhibidores de la succinato deshidrogenasa (SDHI), los fungicidas actualmente más utilizados en la agricultura en Brasil, actúan bloqueando la enzima succinato deshidrogenasa (SDH) de los patógenos de las plantas. Sin embargo, los estudios muestran que los SDHI no solo pueden inhibir la actividad de SDH en los hongos objetivo, sino que también bloquean esa actividad en las células humanas. Teniendo en cuenta las implicaciones médicas y agrícolas de SDH, el propósito de esta revisión narrativa es describir la relación entre la exposición a fungicidas SDHI y la regulación epigenética de SDH asociada con el desarrollo de tumores del estro-ma gastrointestinal, feocromocitoma/paraganglioma y cáncer. Los resultados obtenidos con la investigación mostraron que la enzima SDH humana mostró sensibilidad a algunos SDHI probados, lo que puede causar microcefalia y defectos en el desarrollo neurológico. La deficiencia de la actividad de SDH provoca la acumulación de succinato que puede actuar como un oncometabolito que inhibe las dioxigenasas dependientes de hierro y el alfa-cetoglutarato, once translocaciones -TET e histona desmetilasas, induciendo cambios epigenéticos que conducen a múltiples cánceres y otras enfermedades. Por lo tanto, se deben realizar más análisis in vitro e in vivo para evaluar la susceptibilidad a enfermedades influenciadas por el efecto tóxico de los SDHI.

Relationship between BsmI polymorphism and VDR gene methylation profile, gender, metabolic profile, oxidative stress, and inflammation in adolescents / Relación entre polimorfismo BsmI y perfil de metilación del gen VDR, género, perfil metabólico, estrés oxidativo e inflamación en adolescentes

Background: the biological activity of vitamin D depends on the activity of its receptor or VDR. On the other hand, the activity of this receptor is influenced by its state of methylation. The objective of this study was to verify if the BsmI polymorphism of the VDR gene influences its methylation profile in adolescents. Secondly, it was to verify if the status of some metabolic factors (oxidative stress, inflammation, lipid profile, and glycemia) in the serum, and gender-adjusted vitamin D levels are independent factors with an influence on the VDR methylation profile. Methods and results: the study included 198 adolescents of both sexes, aged 15-19 years, who underwent testing for VDR gene methylation polymorphisms, serum vitamin D levels, and metabolic, oxidative stress, and systemic inflammation markers. It was observed that the BB genotype was less methylated than the other groups (26.1 % versus 30.3 %, and 29.3 % for Bb and bb, respectively), although without statistical differences between them. The odds ratio indicated a protection of 13 % (partially methylated) for vitamin D status, while alpha glycols increased the risk ratio (of being partially methylated) by 3 %. MDA was protective at a 28 % chance of risk that adolescents with higher levels of lipid peroxidation would be hypomethylated. Conclusion: we conclude that the methylation profile of the VDR gene is not influenced by the different BsmI polymorphism genotypes, and that serum vitamin D and serum markers of oxidative stress and inflammation can modulate this profile. (AU)

Antecedentes: la actividad biológica de la vitamina D depende de la actividad de su receptor, el VDR. Por otro lado, la actividad de este receptor está influenciada por su estado de metilación. El objetivo de este estudio es verificar si el polimorfismo BsmI del gen VDR influye en el perfil de metilación del mismo en los adolescentes. En segundo lugar, verificar si los factores metabólicos (estrés oxidativo, inflamación, perfil lipídico y glucemia) del suero y la vitamina D ajustada por sexo actúan independientemente de los polimorfismos sobre el perfil de metilación del VDR. Métodos y resultados: el estudio incluyó a 198 adolescentes de ambos sexos, de 15 a 19 años de edad, que se sometieron a análisis de polimorfismos de metilación del gen VDR, niveles de vitamina D, marcadores metabólicos, estrés oxidativo e inflamación sistémica. Se observó que el genotipo BB estaba menos metilado que los otros grupos (26,1 % contra 30,3 % y 29,3 % para Bb y bb respectivamente), aunque sin diferencias estadísticas entre ellos. El odds ratio indicó una protección del 13 % (parcialmente metilado) para el estado de la vitamina D, mientras que los alfa glicoles aumentaron el índice de riesgo (de estar parcialmente metilado) en un 3 %. La MDA fue protectora con un 28 % de probabilidad de riesgo de que los adolescentes con niveles más altos de peroxidación lipídica fueran hipometilados. Conclusión: concluimos que el perfil de metilación del gen VDR no está influenciado por los diferentes genotipos del polimorfismo BsmI y que la vitamina D y los marcadores de estrés oxidativo e inflamación en el suero pueden modular este perfil. (AU)

Epigenética del cáncer colorrectal / Epigenetics of Colorectal Cancer

Resumen El cáncer colorrectal (CCR) es una enfermedad con una amplia distribución geográfica, que afecta a millones de personas en el mundo. Esta neoplasia se presenta de manera esporádica en el 80% de los casos, el porcentaje restante tiene una historia familiar. Las alteraciones epigenéticas, como la metilación del ADN, modificación de las histonas y los ácidos ribonucleicos (ARN) no codificantes, están involucradas en el desarrollo de esta enfermedad. En la actualidad, estas alteraciones tienen un potencial valioso como biomarcadores para la detección temprana del CCR y se considera que podrían ser útiles para el diagnóstico y pronóstico de los individuos con CCR. El propósito de esta revisión es describir los principales mecanismos epigenéticos involucrados en el cáncer colorrectal, que tienen una función importante en el desarrollo y progresión de la enfermedad.

Abstract Colorectal cancer (CRC) has broad geographic distribution and affects millions of people throughout the world. It occurs sporadically in 80% of cases, but the rest have family histories. Epigenetic alterations such as DNA methylation and modification of histones and non-coding RNA are involved in the development of this disease. At present, these alterations have valuable potential as biomarkers for early detection of CRC and could be useful for diagnosis and determination of prognosis for individuals with CRC. The purpose of this review is to describe the main epigenetic mechanisms involved in colorectal cancer and the important roles they have in the development and progression of the disease.

Infecciones y alteraciones epigenéticas en cáncer / Infections and epigenetic changes in cancer

La participación de mecanismos epigenéticos, junto con infecciones en etapas tempranas de la vida, moldean lesiones premalignas del cáncer, en particular el cáncer gástrico, uno de los tumores más frecuentes en Chile, Latinoamérica y el mundo. El principal objetivo de este artículo, como parte de la serie de revisiones en torno a mecanismos epigenéticos en el desarrollo de enfermedades crónicas, es actualizar el rol de alteraciones epigenéticas (i.e. metilación del ADN) en el contexto de la infección crónica por H. pylori en las etapas precursoras del cáncer gástrico. Las investigaciones desarrolladas en esta área permiten delinear desafíos e interrogantes, en los cuales la pediatría tiene un papel preponderante en el desarrollo de estrategias de prevención y detección temprana de esta enfermedad.

The role of epigenetics and infectious diseases at early stages of life influence pre-malignant lesions of cancer, in particular, gastric cancer, one of the most frequent tumours in Chile, Latin America, and worldwide. This article examines the role of H.pylori and epigenetic alterations (i.e. DNA methylation) at early stages of gastric cancer and proposes, from the paediatric point of view, strategies for prevention and early detection.

Epigenética y obesidad / Epigenetics and obesity

La evidencia indica que la exposición a diversas condiciones ambientales en etapas tempranas de la vida puede inducir alteraciones persistentes en el epigenoma. Los estudios epigenómicos en sujetos obesos han permitido evaluar el papel de los mecanismos epigenéticos en el origen y desarrollo de la obesidad. La presente revisión aborda estudios que dan cuenta de la asociación entre la obesidad y metilación global del genoma (ADN), analizando el potencial impacto de intervenciones previas y posteriores al nacimiento que afectan la metilación del ADN y la obesidad en etapas más avanzadas de la vida. Estudios realizados principalmente en leucocitos, han logrado identificar sitios del ADN diferencialmente metilados asociados con obesidad. Estudios hasta la fecha no han demostrado que dichos cambios en metilación sean revertidos luego de bajar de peso. Esto contrasta con resultados iniciales en este campo, que sugieren que existirían marcadores epigenéticos presentes desde el nacimiento que permitirían definir el riesgo de obesidad durante el curso de la vida. La evidencia actual sugiere que algunas marcas epigenéticas son modificables, basándonos en la exposición en la vida intrauterina y también por los hábitos dietarios y de actividad fisica durante las etapas del crecimiento y en la adultez. Esto sugiere que existe la oportunidad de intervenir durante la gestación o en la vida posnatal temprana, que modificaría los perfiles epigenéticos desfavorables e idealmente contribuiría a prevenir la obesidad en los sujetos o poblaciones susceptibles.

Current evidence supports the notion that exposure to various environmental conditions in early life may induce permanent changes in the epigenome that persist throughout the life-course. This article focuses on early changes associated with obesity in adult life. A review is presented on the factors that induce changes in whole genome (DNA) methylation in early life that are associated with adult onset obesity and related disorders. In contrast, reversal of epigenetic changes associated with weight loss in obese subjects has not been demonstrated. This contrasts with well-established associations found between obesity related DNA methylation patterns at birth and adult onset obesity and diabetes. Epigenetic markers may serve to screen indivuals at risk for obesity and assess the effects of interventions in early life that may delay or prevent obesity in early life. This might contribute to lower the obesity-related burden of death and disability at the population level. The available evidence indicates that epigenetic marks are in fact modifiable, based on modifications in the intrauterine environment and changes in food intake, physical activity and dietary patterns patterns during pregnancy and early years of adult life. This offers the opportunity to intervene before conception, during pregnancy, infancy, childhood, and also in later life. There must be documentation on the best preventive actions in terms of diet and physical activity that will modify or revert the adverse epigenetic markers, thus preventing obesity and diabetes in suceptible individuals and populations.

Análisis de metilación en los genes supresores de tumores CDKN2B y DBC1 en pacientes colombianos con diagnóstico de leucemia / Methylation analysis of the CDKN2B and DBC1 tumour suppressor genes in leukaemia patients in Colombia

Objetivo: Analizar la metilación en los promotores de los genes CDKN2B y DBC1 en muestras de pacientes con leucemia linfoblástica aguda (LLA), leucemia mieloblástica aguda (LMA) y leucemia mieloide crónica (LMC). Además, correlacionar el perfil de metilación de los pacientes con los hallazgos citogenéticos. Materiales y métodos: Se evaluaron 56 pacientes con leucemias: 24 con LLA, 16 con LMA y 16 con LMC. El ADN extraído se modificó con bisulfito de sodio. Se realizó un análisis de metilación en los genes CDKN2B y DBC1 mediante la PCR específica de metilación (MS-PCR). Las muestras positivas por la técnica MS-PCR fueron secuenciadas. Resultados: Se encontró una frecuencia total de metilación del 87,5%. El gen CDKN2B se encontró metilado en el 75% de LLA y de LMC, y del 62% en LMA. El gen DBC1 se encontró metilado en el 96% de LLA, el 94% de LMA y del 68,8% en LMC. El gen más frecuentemente metilado en todas las muestras fue DBC1. De los tres tipos de leucemias, la LLA fue la que presentó los mayores porcentajes de metilación. El 62,5% de la muestras tenían metilado ambos genes. Las muestras con cariotipo normal presentaron una alta frecuencia de metilación de CDKN2B y DBC1. Conclusiones: En este estudio se demostró, por primera vez en pacientes colombianos con leucemias, que la metilación de los genes CDKN2B y DBC1 es un evento frecuente. Los hallazgos indican que la metilación de genes supresores de tumores es una vía molecular alterna que podría estar relacionada con el desarrollo de neoplasias hematológicas.

Objective: To perform a methylation analysis in the CDKN2B and DBC1 gene promoters in samples from Colombian patients with acute lymphoblastic leukaemia (ALL), acute myeloid leukaemia (AML), and chronic myeloid leukaemia (CML), and to correlate the methylation profile with cytogenetic findings. Material and methods: The study included a total of 56 bone marrow samples, 24 from patients with ALL, 16 from AML patients, and 16 from CML patients. DNA was extracted from these samples and converted with sodium bisulphite. Methylation analysis was performed using methylation specific PCR (MS-PCR). The samples that were positive for MS-PCR were sequenced to confirm the results. Results: A total methylation frequency of 87.5% was found. CDKN2B gene promoter hypermethylation was found in 75% of ALL and CML samples, and 62% in AML; while DBC1 gene promoter hypermethylation was found in 96% of the samples of ALL, 94% of AML, and in 68.8% of CML. The most frequently methylated gene in all samples was DBC1. ALL was the type of leukaemia that had the highest percentages of methylation. Almost two-thirds (62.5%) of the samples had both methylated genes. Samples with normal karyotype had a high frequency of methylation in CDKN2B and DBC1 genes. Conclusions: This study showed, for the first time in Colombian patients with leukaemia, that methylation of DBC1 and CDKN2B genes is a common event. Our findings indicate that methylation of tumour suppressor genes is an alternate genetic pathway related to the development of haematological malignancies.

Epigenética: vieja palabra, nuevos conceptos / Epigenetic: an Old Word, New Concepts

La epigenética es el cambio en la expresión de genes sin alteraciones en la secuencia del ADN. Implica una serie de mecanismos tales como la metilación de citosinas del ADN, el empaquetamiento del ADN a través de las modificaciones postraduccionales de las histonas y los microARNs. Los factores que regulan estos me­canismos son muy diversos y van desde la dieta, medio ambiente, hábitos, estrés, comportamiento, conducta, etc. Rev Argent Endocrinol Metab 51:66-74, 2014 Los autores declaran no poseer conflictos de interés.

Epigenetics is defined as changes in gene expression that are not caused by changes in the DNA sequence. It involves a number of mechanisms such as: DNA methylation, DNA packaging through post-translational modifications of histones and microRNAs. The factors that regulate these mechanisms are very diverse, including diet, environment, habits, stress, behavior, etc. Rev Argent Endocrinol Metab 51:66-74, 2014 No financial conflicts of interest exist.

Metilación del ADN: implicaciones en carcinogénesis / DNA methylation and implications in carcinogenesis

El cáncer se ha constituido en uno de los principales problemas de la salud pública mundial, no solo por su casuística sino por la alta morbilidad y mortalidad asociadas; solo en 2008 se estimaron más de 12 millones de nuevos casos de cáncer diagnosticados, 7 millones de muertes y 25 millones de personas vivas con este padecimiento. A nivel celular y molecular, el cáncer se define como una alteración de los mecanismos que regulan la división celular. Entre estos mecanismos, la epigenética estudia los cambios heredables que afectan el patrón de la expresión génica, que no son consecuencia de alteraciones en la secuencia nucleotídica del gen (mutaciones), o de sus secuencias reguladoras (promotores). De estos cambios, la metilación del ADN es la mejor caracterizada, asociándose con el silenciamiento o sobreexpresión de genes claves en la regulación del inicio y la progresión del cáncer, como es el caso de los genes involucrados en la vía de señalización Wnt/β-catenina. Comprender los pasos implicados en el inicio y en el establecimiento de alteraciones en la expresión génica mediadas por fenómenos epigenéticos, permitirá desarrollar terapias dirigidas a componentes claves involucrados en este proceso. En el presente manuscrito se analizan algunos mecanismos epigenéticos, su efecto sobre la regulación de la expresión génica, y su papel en la carcinogénesis.

Cancer has become one of the main public health problems worldwide, not only for its incidence, but also due to its high morbidity and mortality. Only in 2008, an estimated 12 million new cancer cases were diagnosed, with 7 million deaths and 25 million people living with the disease. On a cellular and molecular level, cancer is defined as an alteration in the mechanisms regulating cell division. Epigenetics is the study of inheritable changes affecting the gene expression pattern in these mechanisms, which are not a consequence of alterations in the nucleotide sequence of the gene (mutations) or its regulatory sequences (promoters). Among these changes, DNA methylation has been characterized most accurately. It has been associated with the silencing or overexpression of genes performing a key role in regulating the start and progress of cancer, such as the genes involved in the Wnt/β-catenin signaling pathway. Understanding the steps involved in the start and establishment of gene expression alterations mediated by epigenetic phenomena, will make it possible to develop therapies aimed at key components of this process. The present study is an analysis of some epigenetic mechanisms, their effect on gene expression regulation, and their role in carcinogenesis.

Influencia de las modificaciones epigenéticasocasionadas por el consumo de cigarrillos en relación con la disminución del hueso alveolar-revisión de la literatura / Epigenetic influence of changes caused by cigarette consumption in relation to the bone reduction alveolar-literature review

La epigenética hoy en día constituye uno de los temas de mayor interés en el campo científico, debido a la relación que se ha encontrado con cambios fenotípicos, siendo la metilación del ADN y la desacetilación de las histonas los principales eventos que la caracterizan. A su vez, se ha evidenciado en una amplia gama de patologías. Es por esto, que los factores que inducen estos cambios epigenéticos pueden ser ambientales (como el cigarrillo) o hereditarios. Hay que destacar que entre las alteraciones en las que se ha visto involucrada a la epigenética se encuentra disminución en la cantidad y calidad del hueso en el complejo maxilar-mandíbula, los cuales, a su vez son considerados parámetros de vital importancia en tratamientos odontológicos rehabilitadores. El objetivo de la presente investigación realizar una revisión a la literatura actualizada con el propósito de describir la influencia de las modificaciones epigenéticas ocasionadas por el consumo de cigarrillos y su asociación con la resorción ósea alveolar.

In the present time, the epigenetics is one of the topics with most interest on the scientific field, due to the relationship that has been found with phenotypic changes, been epigenetic´s main event the DNA methylation and the Histone acetylation, that at the same time have been evidenced on a great quantity of pathologies. Because of this, the epigenetics changes are induced by environmental (like smoking) and hereditary factors. Is worth to mention, that among the alterations on which the epigenetic has been related is found the decrease en the quality and quantity of the bone on the maxillary-mandibular complex, which are also consider important parameters for successful dental rehabilitators treatments. A current bibliographic revision was made with the purpose of describe the influence of epigenetic´s modifications involved on the smoking in relationships with the of the alveolar bone loss.

Impronta Genómica y Desarrollo Embrionario / Genomic Imprinting and Embryonic Development

En los organismos diploides, cada gen autosómico está representado por dos copias, o alelos, heredados de cada progenitor al momento de la fecundación. Para la gran mayoría de los genes la expresión ocurre desde ambos alelos de manera simultánea. Sin embargo, un número reducido de genes (menos del 1%) es afectado por un proceso de impronta genómica. Este proceso determina que la expresión del gen sea dependiente del origen parental, es decir, se comporte de manera distinta si su origen es materno o paterno. La metilación del ADN es una de las modificaciones epigenéticas mejor estudiadas y su participación resulta esencial durante el establecimiento de la impronta genómica. Si bien los patrones de metilación a nivel genómico son estables y heredables, existen al menos dos períodos del desarrollo embrionario de mamíferos durante los cuales los patrones de metilación globales son borrados y re-establecidos. Estos dos períodos del desarrollo coinciden con el borrado y establecimiento de la impronta genómica específica de cada individuo. Desde el punto de vista funcional, la mayoría de los genes sometidos a impronta cumplen roles en el control del crecimiento y desarrollo embrionario y placentario. Alteraciones en el patrón de expresión de ellos han sido relacionados a patologías tales como el Síndrome de Algelman y el Síndrome de Prader-Willi, entre otros.

In diploid organisms, autosomal genes are composed of two copies, or alleles, inherited from both parents at fertilization. For the vast majority of autosomal genes, expression occurs from both alleles simultaneously. However, a small proportion (<1%) of genes are imprinted, meaning that their expression depends on the parental origin . DNA methylation is one of the most known epigenetic modifications and its function is critical for the establishment of imprinting. The global pattern of genomic methylation is stable and inheritable, however, it is erased and re-established in a sex-depended manner at two critical periods of embryonic development. Functionally, the majority of imprinted genes play roles in the control of embryonic and placental growth and development. Alterations in imprinted genes have been correlated with several pathologies including the Angelman and Prader-Willi syndromes.

Epigenética: definición, bases moleculares e implicaciones en la salud y en la evolución humana / Epigenetics: definition, molecular bases and implications in human health and evolution / Epigenética: definição, bases moleculares e implicações na saúde e na evolução humana

La Epigenética se refiere a los cambios heredables en el ADN e histonas que no implican altera ciones en la secuencia de nucleótidos y modifican la estructura y condensación de la cromatina por lo que afectan la expresión génica y el fenotipo. Las modificaciones epigenéticas son metilación del ADN y modificaciones de histonas. Objetivo: hacer una revisión de la literatura sobre e concepto de epigenética y su impacto en la salud. Materiales y métodos: se realizó una revisión de la bibliografía sobre el concepto de epigenética, sus bases biológicas, el impacto sobre la salud y la enfermedad y su relación con la evolución. Resultados: los mecanismos epigenéticos ha cobrado cada vez más importancia debido a la creciente asociación con enfermedades compleja y comunes, así como por su impacto en la salud de generaciones futuras y en la evolución humana. Conclusiones: la Epigenética tiene un claro impacto en la salud del individuo, en la de su descendencia y en la evolución de la especie humana.

Epigenetics refers to inheritable changes in DNA and histones that do not involve changes in the sequence of nucleotides and that modifies structure and chromatin condensation, thus affecting gene expression and phenotype. Epigenetic modifications are DNA methylation and histone modifications. Objective: A review of the literature on the concept of Epigenetics and its impact on health. Materials and methods: A review of the literature was performed on the concept of epigenetics, its biological basis, the impact on health and disease and its relation to evolution. Results: Epigenetic mechanisms have become increasingly important because of the growing association with common complex diseases as well as its impact on health of future generations and in human evolution. Conclusions: Epigenetics has a clear impact on the health of individuals in their offspring and with the evolution of the human species.

A Epigenética refere-se às mudanças hereditárias no ADN e histonas que não implicam alterações nas sequencia de nucleotídeos e modificam a estrutura e condensação da cromatina, pelo que afetam a expressão gênica e o fenótipo. As modificações epigenéticas são metilação do ADN e modificações de histonas. Objetivo: fazer uma revisão da literatura sobre o conceito de epigenética e seu impacto na saúde. Materiais e métodos: realizou-se uma revisão da bibliografia sobre o conceito de epigenética, suas bases biológicas, o impacto sobre a saúde e a doença e sua relação com a evolução. Resultados: os mecanismos epigenéticos têm adquirido cada vez mais importância devido à crescente associação com doenças complexas e comunes, assim como por seu impacto na saúde de gerações futuras e na evolução humana. Conclusões: a Epigenética tem um impacto evidente na saúde do individuo, na sua descendência e na evolução da espécie humana.

GADD45α MODULATES DNA METHYLATION INDUCED BY DNA DAMAGE DURING HOMOLOGOUS RECOMBINATION / GADD45α MODULA LA METILACIÓN DEL ADN INDUCIDO POR EL DAÑO DEL ADN DURANTE LA RECOMBINACIÓN HOMÓLOGA

Homologous recombination is one of the major pathways for repairing DNA double strand breaks, the most deleterious of DNA lesions. Recent studies suggest that DNA methylation events target homologous recombination segments; however, the underlying mechanism of DNA methylation during homologous recombination is not understood. In this work, we show that GADD45α, a protein involved in cell cycle control, growth arrest, and apoptosis, plays some role in the epigenetic of homologous recombination. Specifically, it is suggested that dimerization of GADD45α monomers is required. Several point mutants of GADD45α were constructed and analyzed to show defects in self-association. Among them, the GADD45α mutant, CE83AA, lacked the ability to dimerize or oligomerize, which suppressed DNA methylation at homologous recombination sites in vivo. Based on this, we propose a model in which the dimerization (or oligomerization) of GADD45α is involved in strand specific DNA methylation that attends homologous recombination.

La recombinación homóloga es una de las principales vías para la reparación de la ruptura de doble cadena del ADN, la más grave de las lesiones del ADN. Estudios recientes sugieren que la metilación del ADN apunta hacia segmentos de recombinación homóloga; sin embargo, el mecanismo de metilación del ADN durante la recombinación homóloga no es claro. En este estudio, mostramos que GADD45α, una proteína que se encuentra relacionada con el control del ciclo celular, el ceso del crecimiento y la apoptosis, juega un papel en la epigenética de la recombinación homóloga. Específicamente, se ha sugerido que es requerido un dímero de monómeros de GADD45α. Varios puntos mutantes de GADD45α fueron construidos y analizados para mostrar defectos en la libre asociación. Entre ellos, el mutante GADD45α, CE83AA, carecía de la habilidad de dimerización u oligomerización, lo cual suprimió in vivo la metilación del ADN en los sitios de recombinación homóloga. Con base en esto, proponemos un modelo en el cual la dimerización (u oligomerización) de GADD45α está involucrada en la cadena específica de metilación del ADN que lleva a la recombinación homóloga.