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The nuclear envelope is composed by an outer nuclear membrane and an inner nuclear membrane, which is underlain by the nuclear lamina that provides the nucleus with mechanical strength for maintaining structure and regulates chromatin organization for modulating gene expression and silencing. A layer of heterochromatin is beneath the nuclear lamina, attached by inner nuclear membrane integral proteins such as Lamin B receptor (LBR). LBR is a chimeric protein, having also a sterol reductase activity with which it contributes to cholesterol synthesis. Lukasova et al. showed that when DNA is damaged by ɣ-radiation in cancer cells, LBR is lost causing chromatin structure changes and promoting cellular senescence. Cellular senescence is characterized by terminal cell cycle arrest and the expression and secretion of various growth factors, cytokines, metalloproteinases, etc., collectively known as senescence-associated secretory phenotype (SASP) that cause chronic inflammation and tumor progression when they persist in the tissue. Therefore, it is fundamental to understand the molecular basis for senescence establishment, maintenance and the regulation of SASP. The work of Lukasova et al. contributed to our understanding of cellular senescence establishment and provided the basis that lead to the further discovery that chromatin changes caused by LBR reduction induce an up-regulated expression of SASP factors. LBR dysfunction has relevance in several diseases and possibly in physiological aging. The potential bifunctional role of LBR on cellular senescence establishment, namely its role in chromatin structure together with its enzymatic activity contributing to cholesterol synthesis, provide a new target to develop potential anti-aging therapies.

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RESUMEN

El asma es una enfermedad respiratoria crónica con alta heredabilidad. Se ha propuesto que en supatogénesis participan varios genes con efectos variables al igual que factores ambientales, y se hasugerido que los mecanismos epigenéticos pueden mediar parte del efecto de los factores ambientalesen el comienzo y la evolución de la enfermedad. La epigenética describe los cambios en la expresión génica heredables durante las mitosis y meiosis que no son codificados en la secuencia de ADN. Ellos incluyen la metilación o desmetilación del ADN y la acetilación, desacetilación,ubiquitinación, sumoilación y fosforilación de histonas, cambios en los microARN y alteraciones cromatónicas. En esta revisión se describen hallazgos que establecen una relación entre algunos mecanismos epigenéticos y el proceso inflamatorio y la exposición a factores ambientales en elasma.Ellos incluyen: el aumento en la actividad de las acetilasas de histonas y de la expresión de las enzimas acetiladoras; la disminución de las enzimas desacetiladoras en los pulmones de individuos asmáticos; el aumento de la expresión del factor nuclear NF-¦ÊB durante el proceso inflamatorioal¨¦rgico; cambios en la metilación/desmetilación del ADN durante la diferenciación de los linfocitosy la estimulación/supresión de genes como los de la IL-4 y el IFN-¦Ã, respectivamente. El humo delcigarrillo, las infecciones bacterianas y virales, la dieta materna y la polución ambiental son otros factores que desencadenan procesos epigenéticos como la acetilación de histonas, la inducción decitoquinas inflamatorias, la inactivación de las desacetilasas de histonas, la polarización de la respuesta inmune hacia el tipo Th2 y una mayor producción de IgE y citoquinas de este perfil.

Epigenetics in asthma is a chronic respiratory disease with a highheritability. It has been postulated that several genes withvariable effects are involved in its pathogenesis alongwith environmental factors. It has been suggested thatepigenetic mechanisms can mediate the effects ofenvironmental factors on the onset and progression ofthe disease. Epigenetics describes inheritable changes ingene expression inherited during meiosis and mitosis thatare not encoded in the DNA sequence. They include DNAmethylation/ demethylation, acetylation, deacetylation,ubiquitination, SUMOylation and phosphorylation ofhistones, changes in microARN and alterations ofchromatine. In this article we review some findings thatestablish a relationship between some epigeneticmechanisms and the inflammatory process in asthmaand exposure to environmental factors. They includeincreasing the activity of histone acetyl-transferases andthe expression of histone acetylating enzymes, decreaseof deacetylating enzymes in the lungs of asthmatics;increased expression of the transcription factor NF-¦ÊB inthe allergic inflammatory process, changes inmethylation/demethlylation of DNA during thedifferentiation of lymphocytes and the stimulation/suppression of IL-4 and IFN¦Ã genes, respectively.Smoking, bacterial and viral infections, maternal diet andenvironmental pollution are also factors that triggerepigenetic processes such as histone acetylation andinduction of inflammatory cytokines, inactivation ofhistone deacetytransferases, polarization of the immuneresponse toward the Th2 type and increased productionof IgE and cytokines of this profile.

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