Epigenetics and Autoimmune Diseases

Epigenetics is defined as the study of all inheritable and potentially reversible changes in genome function that do not alter the nucleotide sequence within the DNA. Epigenetic mechanisms such as DNA methylation, histone modification, nucleosome positioning, and microRNAs (miRNAs) are essential to carry out key functions in the regulation of gene expression. Therefore, the epigenetic mechanisms are a window to understanding the possible mechanisms involved in the pathogenesis of complex diseases such as autoimmune diseases. It is noteworthy that autoimmune diseases do not have the same epidemiology, pathology, or symptoms but do have a common origin that can be explained by the sharing of immunogenetic mechanisms. Currently, epigenetic research is looking for disruption in one or more epigenetic mechanisms to provide new insights into autoimmune diseases. The identification of cell-specific targets of epigenetic deregulation will serve us as clinical markers for diagnosis, disease progression, and therapy approaches

Epigenetics and autoimmune diseases

Epigenetics is defined as the study of all inheritable and potentially reversible changes in genome function that do not alter the nucleotide sequence within the DNA. Epigenetic mechanisms such as DNA methylation, histone modification, nucleosome positioning, and microRNAs (miRNAs) are essential to carry out key functions in the regulation of gene expression. Therefore, the epigenetic mechanisms are a window to understanding the possible mechanisms involved in the pathogenesis of complex diseases such as autoimmune diseases. It is noteworthy that autoimmune diseases do not have the same epidemiology, pathology, or symptoms but do have a common origin that can be explained by the sharing of immunogenetic mechanisms. Currently, epigenetic research is looking for disruption in one or more epigenetic mechanisms to provide new insights into autoimmune diseases. The identification of cell-specific targets of epigenetic deregulation will serve us as clinical markers for diagnosis, disease progression, and therapy approaches

Effectiveness of an intervention for Aedes aegypti control scaled-up under an inter-sectoral approach in a Colombian city hyper-endemic for dengue virus.

Aedes aegypti transmitted arboviral diseases are of significant importance in Colombia, particularly since the 2014/2015 introduction of chikungunya and Zika in the Americas and the increasing spread of dengue. In response, the Colombian government initiated the scaling-up of a community-based intervention under inter and multi-sector partnerships in two out of four sectors in Girardot, one of the most hyper-endemic dengue cities in the country. Using a quasi-experimental research design a scaled-up community-led Aedes control intervention was assessed for its capacity to reduce dengue from January 2010 to August 2017 in Girardot, Colombia. Reported dengue cases, and associated factors were analysed from available data sets from the Colombian disease surveillance systems. We estimated the reduction in dengue cases before and after the intervention using, Propensity Score Matching and an Autoregressive Moving Average model for robustness. In addition, the differences in dengue incidence among scaling-up phases (pre-implementation vs sustainability) and between treatment groups (intervention and control areas) were modelled. Evidence was found in favour of the intervention, although to maximise impact the scaling-up of the intervention should continue until it covers the remaining sectors. It is expected that a greater impact of the intervention can be documented in the next outbreak of dengue in Girardot

THBD sequence variants potentially related to recurrent pregnancy loss

Recurrent pregnancy loss (RPL) is a frequently occurring disease, which is classified as idiopathic in more than 50% of cases. THBD, the endothelial cell receptor for thrombin, has been associated with distinct biological processes and considered a coherent RPL-related candidate gene. In the present study, we have sequenced the complete coding region of THBD in 262 patients affected by RPL. Bioinformatics analysis and screening of controls strongly suggested that the THBD-p.Trp153Gly mutation might be related to RPL aetiology. It could be used, after its validation by functional assays, as a molecular marker for diagnostic/prognostic purposes. © 2017 The Author(s)

FOXD1 mutations are related to repeated implantation failure, intra-uterine growth restriction and preeclampsia

Background: Human reproductive disorders consist of frequently occurring dysfunctions including a broad range of phenotypes affecting fertility and women's health during pregnancy. Several female-related diseases have been associated with hypofertility/infertility phenotypes, such as recurrent pregnancy loss (RPL). Other occurring diseases may be life-threatening for the mother and foetus, such as preeclampsia (PE) and intra-uterine growth restriction (IUGR). FOXD1 was defined as a major molecule involved in embryo implantation in mice and humans by regulating endometrial/placental genes. FOXD1 mutations in human species have been functionally linked to RPL's origin. Methods: FOXD1 gene mutation screening, in 158 patients affected by PE, IUGR, RPL and repeated implantation failure (RIF), by direct sequencing and bioinformatics analysis. Plasmid constructs including FOXD1 mutations were used to perform in vitro gene reporter assays. Results: Nine non-synonymous sequence variants were identified. Functional experiments revealed that p.His267Tyr and p.Arg57del led to disturbances of promoter transcriptional activity (C3 and PlGF genes). The FOXD1 p.Ala356Gly and p.Ile364Met deleterious mutations (previously found in RPL patients) have been identified in the present work in women suffering PE and IUGR. Conclusions: Our results argue in favour of FOXD1 mutations' central role in RPL, RIF, IUGR and PE pathogenesis via C3 and PlGF regulation and they describe, for the first time, a functional link between FOXD1 and implantation/placental diseases. FOXD1 could therefore be used in clinical environments as a molecular biomarker for these diseases in the near future. Recurrent pregnancy loss, Preeclampsia, Intra-uterine growth restriction, FOXD1. © 2019 The Author(s)

Association of the DNMT3B -579G>T polymorphism with risk of thymomas in patients with myasthenia gravis

Increasing evidence suggests a contribution of epigenetic processes in promoting cancer and autoimmunity. Myasthenia gravis (MG) is an autoimmune disease mediated, in approximately 80% of the patients, by antibodies against the nicotinic acetylcholine receptor (AChR+). Moreover, epithelial tumours (thymomas) are present in about 10-20% of the patients, and there is indication that changes in DNA methylation might contribute to the risk and progression of thymomas. However, the role of epigenetics in MG is still not completely clarified. In the present study we investigated if a common polymorphism (-579G>T: rs1569686) in the promoter of the DNMT3B gene coding for the DNA methyltransferase 3B, an enzyme that mediates DNA methylation, increases the risk to develop MG or MG-associated thymomas. The study polymorphism was selected based on recent reports and a literature meta-analysis suggesting association with increased risk of various types of cancer. We screened 324 AChR+ MG patients (140 males and 184 females, mean age 56.0 \ub1 16.5 years) and 735 healthy matched controls (294 males and 441 females, mean age 57.3 \ub1 15.6 years). 94 of the total MG patients had a thymoma. While there was no association with the whole cohort of MG patients, we found a statistically significant association of the DNMT3B-579T allele (OR = 1.51; 95% CI=1.1-2.1, P = 0.01) and the TT homozygous genotype (OR = 2.59; 95% CI=1.4-4.9, P = 0.006) with the risk of thymoma. No association was observed in MG patients without thymoma, even after stratification into clinical subtypes. Present results suggest that the DNMT3B-579T allele might contribute to the risk of developing thymoma in MG patients, particularly in homozygous TT subjects

Aging and computational systems biology

This is the peer reviewed version of the following article: Mooney, K. M., Morgan, A. E., & Mc Auley, M. T. (2016). Aging and computational systems biology. Wiley Interdisciplinary Reviews: Systems Biology and Medicine, 8(2), 123-139, which has been published in final form at doi10.1002/wsbm.1328. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Self-ArchivingAging research is undergoing a paradigm shift, which has led to new and innovative methods of exploring this complex phenomenon. The systems biology approach endeavors to understand biological systems in a holistic manner, by taking account of intrinsic interactions, while also attempting to account for the impact of external inputs, such as diet. A key technique employed in systems biology is computational modeling, which involves mathematically describing and simulating the dynamics of biological systems. Although a large number of computational models have been developed in recent years, these models have focused on various discrete components of the aging process, and to date no model has succeeded in completely representing the full scope of aging. Combining existing models or developing new models may help to address this need and in so doing could help achieve an improved understanding of the intrinsic mechanisms which underpin aging

Genómica funcional y disección molecular de FOXD1 para la identificación de nuevos biomarcadores genéticos asociados a patologías de la reproducción de origen endometrial y placentario

El aborto espontáneo recurrente (AER) se define como dos o más pérdidas consecutivas de la gestación antes de la semana 20 del desarrollo intrauterino. Esta patología afecta a aproximadamente entre el 1% y el 5% de las parejas. La etiología del AER se puede dividir en causas no-genéticas como genéticas. Sin embargo, ~50% de los casos se considera idiopático. De manera análoga, la etiología molecular de la falla de implantación recurrente (FIR), definida como la falla de la implantación en al menos 2 o más ciclos consecutivos de fertilización in vitro, es poco conocida. La etiología molecular del AER y de la FIR está asociada potencialmente a variantes de secuencia en cientos de genes candidato que participan en las cascadas moleculares fisiológicas de la implantación y durante toda la gestación. La aproximación gen candidato, usando la secuenciación de Sanger, ha sido de utilidad para la descripción de pocos genes implicados en el AER. La secuenciación de siguiente generación (NGS) ha sido una herramienta eficiente puesto que permite el estudio simultáneo de múltiples genes relacionados con enfermedades complejas. En la primera parte de este trabajo de tesis se utilizó la aproximación NGS-exoma para identificar nuevos genes y mutaciones potencialmente implicadas en el desarrollo del AER. Algunas de las mutaciones encontradas por este abordaje fueron estudiadas mediante ensayos funcionales in vitro para determinar su posible efecto deletéreo. La identificación de la variante THBD p.Trp153Gly en mujeres colombianas con AER y su validación mediante ensayos funcionales in vitro sugiere, por primera vez, una relación directa entre formas mutantes de esta proteína y la fisiopatología del AER, considerándose como un posible marcador molecular para el diagnóstico en pacientes colombianas con AER idiopático. En la segunda parte del presente trabajo de tesis identificamos y estudiamos funcionalmente nuevas mutaciones de FOXD1, un gen relevante en la fisiología endometrial y placentaria, identificadas en pacientes FIR, AER, preeclampsia (PE) y retardo del crecimiento intrauterino (RCIU). Los ensayos funcionales in vitro demostraron que las mutaciones FOXD1-p.His267Tyr y FOXD1-p.Arg57del. modifican la transactivación del promotor de C3, contribuyendo con el fenotipo. FOXD1 podría considerarse en consecuencia un marcador molecular diagnóstico para las pacientes con AER, FIR, RCIU y PE. Por último, ensayos por inmunoprecipitación de la cromatina secuenciación NGS (ChIP-seq) permitieron determinar potenciales nuevos genes blanco directos de FOXD1 (CTSC, CD86, CMA1 y TRPC6) en un contexto placentario. La información generada durante este trabajo de tesis aporta al conocimiento sobre el origen genético del AER, la FIR, y el RCIU/PE. Estos resultados podrían ser de utilidad para los especialistas clínicos en el contexto del desarrollo de la medicina traslacional.Recurrent pregnancy loss (RPL) is defined as the loss of two or more consecutive and spontaneous miscarriages before the 20th week of gestation. This pathology affects ~1% to 5% of the couples. The RPL aetiology is classified as non-genetics and genetics. However, the 50% of the cases remains idiopathic. Similarly, the aetiology of the recurrent implantation failure (RIF), defined as the implantation failure in at least 2 or more consecutive cycles of in vitro fertilization (IVF), is poorly understood. To note, the molecular RPL and RIF aetiology is potentially associated with hundreds of genes which participate in the physiological molecular pathways related to the implantation and gestation. The candidate gene approach using Sanger sequencing has been useful to identify some genes associated with RPL. However, the next generation sequencing (NGS) has been an effective tool to overcome this limitation because it allows the simultaneous study of multiple genes related to complex diseases. In first part of this thesis, we used the NGS-exome approach to identify new genes and mutation potentially implicated in the development of RPL. Some of the mutations found by this approach were tested by functional in vitro assays to determine their possible deleterious effect within the pathology. The identification of the variant THBD p.Trp153Gly in Colombian women with RPL and its validation through functional in vitro assays suggested, for the first time, a direct association with the RPL pathophysiology. Therefore, it may be considered as a molecular biomarker for the RPL diagnosis in Colombian patients. In the second part of this thesis, we identified and studied the potential implication of new FOXD1 mutations, a relevant gene in the endometrium and placenta physiology, in patients with RIF, RPL, preeclampsia (PE) and intrauterine growth restriction (IUGR). The functional in vitro assays demonstrated that FOXD1 p.His267Tyr and FOXD1 p.Arg57del mutations modify the C3 promoter transactivation, thus contributing to the phenotype. Therefore, FOXD1 could be considered a molecular biomarker for the diagnosis of RPL, RIF, PE and IUGR patients. The chromatin immunoprecipitation assays (ChIP) allowed to determine new direct FOXD1 target genes (CTSC, CD86, CMA1 y TRPC6) within the placenta context. The information generated during this thesis contributes to the general knowledge about the origin and development of RPL, RIF, PE/IUGR. These results might be useful for the clinical specialist in a context of translational medicine.2021-01-29 01:01:01: Script de automatizacion de embargos. info:eu-repo/date/embargoEnd/2021-01-2

Genómica funcional y disección molecular de FOXD1 para la identificación de nuevos biomarcadores genéticos asociados a patologías de la reproducción de origen endometrial y placentario

El aborto espontáneo recurrente (AER) se define como dos o más pérdidas consecutivas de la gestación antes de la semana 20 del desarrollo intrauterino. Esta patología afecta a aproximadamente entre el 1% y el 5% de las parejas. La etiología del AER se puede dividir en causas no-genéticas como genéticas. Sin embargo, ~50% de los casos se considera idiopático. De manera análoga, la etiología molecular de la falla de implantación recurrente (FIR), definida como la falla de la implantación en al menos 2 o más ciclos consecutivos de fertilización in vitro, es poco conocida. La etiología molecular del AER y de la FIR está asociada potencialmente a variantes de secuencia en cientos de genes candidato que participan en las cascadas moleculares fisiológicas de la implantación y durante toda la gestación. La aproximación gen candidato, usando la secuenciación de Sanger, ha sido de utilidad para la descripción de pocos genes implicados en el AER. La secuenciación de siguiente generación (NGS) ha sido una herramienta eficiente puesto que permite el estudio simultáneo de múltiples genes relacionados con enfermedades complejas. En la primera parte de este trabajo de tesis se utilizó la aproximación NGS-exoma para identificar nuevos genes y mutaciones potencialmente implicadas en el desarrollo del AER. Algunas de las mutaciones encontradas por este abordaje fueron estudiadas mediante ensayos funcionales in vitro para determinar su posible efecto deletéreo. La identificación de la variante THBD p.Trp153Gly en mujeres colombianas con AER y su validación mediante ensayos funcionales in vitro sugiere, por primera vez, una relación directa entre formas mutantes de esta proteína y la fisiopatología del AER, considerándose como un posible marcador molecular para el diagnóstico en pacientes colombianas con AER idiopático. En la segunda parte del presente trabajo de tesis identificamos y estudiamos funcionalmente nuevas mutaciones de FOXD1, un gen relevante en la fisiología endometrial y placentaria, identificadas en pacientes FIR, AER, preeclampsia (PE) y retardo del crecimiento intrauterino (RCIU). Los ensayos funcionales in vitro demostraron que las mutaciones FOXD1-p.His267Tyr y FOXD1-p.Arg57del. modifican la transactivación del promotor de C3, contribuyendo con el fenotipo. FOXD1 podría considerarse en consecuencia un marcador molecular diagnóstico para las pacientes con AER, FIR, RCIU y PE. Por último, ensayos por inmunoprecipitación de la cromatina secuenciación NGS (ChIP-seq) permitieron determinar potenciales nuevos genes blanco directos de FOXD1 (CTSC, CD86, CMA1 y TRPC6) en un contexto placentario. La información generada durante este trabajo de tesis aporta al conocimiento sobre el origen genético del AER, la FIR, y el RCIU/PE. Estos resultados podrían ser de utilidad para los especialistas clínicos en el contexto del desarrollo de la medicina traslacional.Recurrent pregnancy loss (RPL) is defined as the loss of two or more consecutive and spontaneous miscarriages before the 20th week of gestation. This pathology affects ~1% to 5% of the couples. The RPL aetiology is classified as non-genetics and genetics. However, the 50% of the cases remains idiopathic. Similarly, the aetiology of the recurrent implantation failure (RIF), defined as the implantation failure in at least 2 or more consecutive cycles of in vitro fertilization (IVF), is poorly understood. To note, the molecular RPL and RIF aetiology is potentially associated with hundreds of genes which participate in the physiological molecular pathways related to the implantation and gestation. The candidate gene approach using Sanger sequencing has been useful to identify some genes associated with RPL. However, the next generation sequencing (NGS) has been an effective tool to overcome this limitation because it allows the simultaneous study of multiple genes related to complex diseases. In first part of this thesis, we used the NGS-exome approach to identify new genes and mutation potentially implicated in the development of RPL. Some of the mutations found by this approach were tested by functional in vitro assays to determine their possible deleterious effect within the pathology. The identification of the variant THBD p.Trp153Gly in Colombian women with RPL and its validation through functional in vitro assays suggested, for the first time, a direct association with the RPL pathophysiology. Therefore, it may be considered as a molecular biomarker for the RPL diagnosis in Colombian patients. In the second part of this thesis, we identified and studied the potential implication of new FOXD1 mutations, a relevant gene in the endometrium and placenta physiology, in patients with RIF, RPL, preeclampsia (PE) and intrauterine growth restriction (IUGR). The functional in vitro assays demonstrated that FOXD1 p.His267Tyr and FOXD1 p.Arg57del mutations modify the C3 promoter transactivation, thus contributing to the phenotype. Therefore, FOXD1 could be considered a molecular biomarker for the diagnosis of RPL, RIF, PE and IUGR patients. The chromatin immunoprecipitation assays (ChIP) allowed to determine new direct FOXD1 target genes (CTSC, CD86, CMA1 y TRPC6) within the placenta context. The information generated during this thesis contributes to the general knowledge about the origin and development of RPL, RIF, PE/IUGR. These results might be useful for the clinical specialist in a context of translational medicine