Epigenetic regulation in aging and gastric cancer

Objetivos: O processo de envelhecimento e a maioria das neoplasias podem ser regulados por alterações epigenéticas, dentre elas a metilação do DNA. Este estudo tem como objetivos: a) analisar a frequência de metilação dos promotores dos genes SIRT1; SIRT3, hTERT, SMARCA5, CDH1, IGFBP3, CAV-1 no envelhecimento e no adenocarcinoma gástrico; b) avaliar a expressão das proteínas codificadas desses genes em tecidos gástricos tumoral e normal; c) associar resultados com dados clinicopatológicos da amostra. Métodos: A frequência de metilação desses genes foi analisada por PCR metilação-específica (MS-PCR) em amostras de linfócitos de jovens e idosos, bem como em adenocarcinoma gástrico e margens normais. A análise da expressão protéica foi realizada por imunoistoquímica. Resultados: Os promotores dos genes SIRT1 e IGFBP-3 apresentaram maior metilação em idosos, quando comparado ao grupo jovem. Além disso, dentre os sete genes estudados, cerca de 85% dos idosos apresentaram quatro ou mais desses genes hipermetilados, enquanto que entre jovens mais de 50% apresentou até três genes metilados (p=0,001). A proteína SIRT1 apresentou uma expressão seis vezes maior em tumores do que em tecido não neoplásico (p=0,0003), já SIRT3 apresentou maior expressão em tecido não neoplásico do que em tumoral (OR=0,313; p=0,005). SIRT3 encontrou-se mais frequentemente hipermetilado quando não havia expressão de sua proteína (p=0,0019). O gene hTERT apresentou-se mais frequentemente hipermetilado em amostras tumorais (p=0,0002) e sua expressão protéica foi observada somente em tumores (p<0,0001). SMARCA5 apresentou maior expressão no tecido neoplásico quando comparado com a margem do tecido gástrico (p<0,001) e a expressão de sua proteína estava associada à ausência de metilação do promotor gênico (p=0,0104). Caveolina-1 também foi mais frequentemente observada em tumores quando comparada ao não neoplásico (p<0,0001), principalmente no tipo intestinal (P=0,0008). A metilação do promotor do gene CAV1 foi associada à ausência de expressão em amostras tumorais (p=0,0001). Para IGFBP-3, foi observado ainda maior expressão em tumores do que em tecido não neoplásico (p<0,0001). CDH1 estava presente em 100% das amostras de tecido não neoplásico, diferindo do tumoral (p<0,0001). Conclusões: No processo do envelhecimento natural, ocorre um aumento da metilação em promotores de genes específicos com a idade, que pode influenciar a expressão gênica. Além disso, no câncer gástrico, as proteínas SIRT1, hTERT, SMARCA5, CDH1, IGFBP-3 e CAV1 apresentaram uma maior expressão, podendo configurar bons biomarcadores e possíveis alvos terapêuticos. SIRT3 foi a única proteína com função protetora contra esse tipo tumoral. A regulação epigenética pela metilação do DNA parece ocorrer em tecido gástrico somente para os genes SIRT3, SMARCA5 e CAV1, porém a análise da metilação dos genes hTERT e CDH1 também pode servir como marcador para a neoplasia estudada.TEDEBV UNIFESP: Teses e dissertaçõe

Regulation of impulsive and aggressive behaviours by a novel lncRNA

14 páginas, 5 figuras. a través de PubMed Central se puede consultar: versión post-print e información suplementaria: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7436429/pdf/nihms-1604033.pdfHigh impulsive and aggressive traits associate with poor behavioural self-control. Despite their importance in predicting behavioural negative outcomes including suicide, the molecular mechanisms underlying the expression of impulsive and aggressive traits remain poorly understood. Here, we identified and characterized a novel long noncoding RNA (lncRNA), acting as a regulator of the monoamine oxidase A (MAOA) gene in the brain, and named it MAOA-associated lncRNA (MAALIN). Our results show that in the brain of suicide completers, MAALIN is regulated by a combination of epigenetic mechanisms including DNA methylation and chromatin modifications. Elevated MAALIN in the dentate gyrus of impulsive-aggressive suicides was associated with lower MAOA expression. Viral overexpression of MAALIN in neuroprogenitor cells decreased MAOA expression while CRISPR-mediated knock out resulted in elevated MAOA expression. Using viral-mediated gene transfer, we confirmed that MAALIN in the hippocampus significantly decreases MAOA expression and exacerbates the expression of impulsive-aggressive behavioural traits in CD1 aggressive mice. Overall, our findings suggest that variations in DNA methylation mediate the differential expression of a novel lncRNA that acts on MAOA expression to regulate impulsive-aggressive behaviours.GT holds a Canada Research Chair (Tier 1) and a NARSAD Distinguished Investigator Award. He is supported by grants from the Canadian Institute of Health Research (CIHR) (FDN148374 and EGM141899), by the FRQS through the Quebec Network on Suicide, Mood Disorders and Related Disorders. BL holds a Sentinelle Nord Research Chair, is supported by a NARSAD young investigator award, a CIHR (SVB397205) and Natural Science and Engineering Research Council (NSERC; RGPIN-2019-06496) grants and receives FRQS Junior-1 salary support; this work was also made possible by resources supported by the Quebec Network on Suicide, Mood Disorders and Related Disorders.Peer reviewe

Mosaic copy number variation in schizophrenia

Recent reports suggest that somatic structural changes occur in the human genome, but how these genomic alterations might contribute to disease is unknown. Using samples collected as part of the International Schizophrenia Consortium (schizophrenia, n=3518; control, n=4238) recruited across multiple university research centers, we assessed single-nucleotide polymorphism genotyping arrays for evidence of chromosomal anomalies. Data from genotyping arrays on each individual were processed using Birdsuite and analyzed with PLINK. We validated potential chromosomal anomalies using custom nanostring probes and quantitative PCR. We estimate chromosomal alterations in the schizophrenia population to be 0.42%, which is not significantly different from controls (0.26%). We identified and validated a set of four extremely large (>10 Mb) chromosomal anomalies in subjects with schizophrenia, including a chromosome 8 trisomy and deletion of the q arm of chromosome 7. These data demonstrate that chromosomal anomalies are present at low frequency in blood cells of both control and schizophrenia subjects

PI3K/AKT/mTOR signaling in gastric cancer : epigenetics and beyond.

PI3K/AKT/mTOR pathway is one of the most important signaling pathways involved in normal cellular processes. Its aberrant activation modulates autophagy, epithelial-mesenchymal transition, apoptosis, chemoresistance, and metastasis in many human cancers. Emerging evidence demonstrates that some infections as well as epigenetic regulatory mechanisms can control PI3K/AKT/mTOR signaling pathway. In this review, we focused on the role of this pathway in gastric cancer development, prognosis, and metastasis, with an emphasis on epigenetic alterations including DNA methylation, histone modifications, and post-transcriptional modulations through non-coding RNAs fluctuations as well as H. pylori and Epstein-Barr virus infections. Finally, we reviewed different molecular targets and therapeutic agents in clinical trials as a potential strategy for gastric cancer treatment through the PI3K/AKT/mTOR pathway. [Abstract copyright: Copyright © 2020 Elsevier Inc. All rights reserved.

Acute exercise leads to regulation of Telomere-Associated genes and MicroRNA expression in immune Cells

Telomeres are specialized nucleoprotein structures that protect chromosomal ends from degradation. These structures progressively shorten during cellular division and can signal replicative senescence below a critical length. Telomere length is predominantly maintained by the enzyme telomerase. Significant decreases in telomere length and telomerase activity are associated with a host of chronic diseases; conversely their maintenance underpins the optimal function of the adaptive immune system. Habitual physical activity is associated with longer leukocyte telomere length; however, the precise mechanisms are unclear. Potential hypotheses include regulation of telomeric gene transcription and/or microRNAs (miRNAs). We investigated the acute exercise-induced response of telomeric genes and miRNAs in twenty-two healthy males (mean age = 24.1±1.55 years). Participants undertook 30 minutes of treadmill running at 80% of peak oxygen uptake. Blood samples were taken before exercise, immediately post-exercise and 60 minutes post-exercise. Total RNA from white blood cells was submitted to miRNA arrays and telomere extension mRNA array. Results were individually validated in white blood cells and sorted T cell lymphocyte subsets using quantitative real-time PCR (qPCR). Telomerase reverse transcriptase (TERT) mRNA (P = 0.001) and sirtuin-6 (SIRT6) (P<0.05) mRNA expression were upregulated in white blood cells after exercise. Fifty-six miRNAs were also differentially regulated post-exercise (FDR <0.05). In silico analysis identified four miRNAs (miR-186, miR-181, miR-15a and miR-96) that potentially targeted telomeric gene mRNA. The four miRNAs exhibited significant upregulation 60 minutes post-exercise (P<0.001). Telomeric repeat binding factor 2, interacting protein (TERF2IP) was identified as a potential binding target for miR-186 and miR-96 and demonstrated concomitant downregulation (P<0.01) at the corresponding time point. Intense cardiorespiratory exercise was sufficient to differentially regulate key telomeric genes and miRNAs in white blood cells. These results may provide a mechanistic insight into telomere homeostasis and improved immune function and physical health. Funding NHMR