Browsing by Subject "PROMOTER METHYLATION"

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  • Castren, Eero; Monteggia, Lisa M. (2021)
    Neurotrophic factors, particularly BDNF (brain-derived neurotrophic factor), have been associated with depression and antidepressant drug action. A variety of preclinical and clinical studies have implicated impaired BDNF signaling through its receptor TrkB (neurotrophic receptor tyrosine kinase 2) in the pathophysiology of mood disorders, but many of the initial findings have not been fully supported by more recent meta-analyses, and more both basic and clinical research is needed. In contrast, increased expression and signaling of BDNF has been repeatedly implicated in the mechanisms of both typical and rapid-acting antidepressant drugs, and recent findings have started to elucidate the mechanisms through which antidepressants regulate BDNF signaling. BDNF is a critical regulator of various types of neuronal plasticities in the brain, and plasticity has increasingly been connected with antidepressant action. Although some equivocal data exist, the hypothesis of a connection between neurotrophic factors and neuronal plasticity with mood disorders and antidepressant action has recently been further strengthened by converging evidence from a variety of more recent data reviewed here.
  • Vehmeijer, Florianne O. L.; Kuepers, Leanne K.; Sharp, Gemma C.; Salas, Lucas A.; Lent, Samantha; Jima, Dereje D.; Tindula, Gwen; Reese, Sarah; Qi, Cancan; Gruzieva, Olena; Page, Christian; Rezwan, Faisal; Melton, Philip E.; Nohr, Ellen; Escaramis, Georgia; Rzehak, Peter; Heiskala, Anni; Gong, Tong; Tuominen, Samuli T.; Gao, Lu; Ross, Jason P.; Starling, Anne P.; Holloway, John W.; Yousefi, Paul; Aasvang, Gunn Marit; Beilin, Lawrence J.; Bergstrom, Anna; Binder, Elisabeth; Chatzi, Leda; Corpeleijn, Eva; Czamara, Darina; Eskenazi, Brenda; Ewart, Susan; Ferre, Natalia; Grote, Veit; Gruszfeld, Dariusz; Haberg, Siri E.; Hoyo, Cathrine; Huen, Karen; Karlsson, Robert; Kull, Inger; Langhendries, Jean-Paul; Lepeule, Johanna; Magnus, Maria C.; Maguire, Rachel L.; Molloy, Peter L.; Monnereau, Claire; Mori, Trevor A.; Oken, Emily; Räikkönen, Katri; Rifas-Shiman, Sheryl; Ruiz-Arenas, Carlos; Sebert, Sylvain; Ullemar, Vilhelmina; Verduci, Elvira; Vonk, Judith M.; Xu, Cheng-jian; Yang, Ivana; Zhang, Hongmei; Zhang, Weiming; Karmaus, Wilfried; Dabelea, Dana; Muhlhausler, Beverly S.; Breton, Carrie; Lahti, Jari; Almqvist, Catarina; Jarvelin, Marjo-Riitta; Koletzko, Berthold; Vrijheid, Martine; Sorensen, Thorkild I. A.; Huang, Rae-Chi; Arshad, Syed Hasan; Nystad, Wenche; Melen, Erik; Koppelman, Gerard H.; London, Stephanie J.; Holland, Nina; Bustamante, Mariona; Murphy, Susan K.; Hivert, Marie-France; Baccarelli, Andrea; Relton, Caroline L.; Snieder, Harold; Jaddoe, Vincent W. V.; Felix, Janine F. (2020)
    Background DNA methylation has been shown to be associated with adiposity in adulthood. However, whether similar DNA methylation patterns are associated with childhood and adolescent body mass index (BMI) is largely unknown. More insight into this relationship at younger ages may have implications for future prevention of obesity and its related traits. Methods We examined whether DNA methylation in cord blood and whole blood in childhood and adolescence was associated with BMI in the age range from 2 to 18 years using both cross-sectional and longitudinal models. We performed meta-analyses of epigenome-wide association studies including up to 4133 children from 23 studies. We examined the overlap of findings reported in previous studies in children and adults with those in our analyses and calculated enrichment. Results DNA methylation at three CpGs (cg05937453, cg25212453, and cg10040131), each in a different age range, was associated with BMI at Bonferroni significance, P <1.06 x 10(-7), with a 0.96 standard deviation score (SDS) (standard error (SE) 0.17), 0.32 SDS (SE 0.06), and 0.32 BMI SDS (SE 0.06) higher BMI per 10% increase in methylation, respectively. DNA methylation at nine additional CpGs in the cross-sectional childhood model was associated with BMI at false discovery rate significance. The strength of the associations of DNA methylation at the 187 CpGs previously identified to be associated with adult BMI, increased with advancing age across childhood and adolescence in our analyses. In addition, correlation coefficients between effect estimates for those CpGs in adults and in children and adolescents also increased. Among the top findings for each age range, we observed increasing enrichment for the CpGs that were previously identified in adults (birth P-enrichment = 1; childhood P-enrichment = 2.00 x 10(-4); adolescence P-enrichment = 2.10 x 10(-7)). Conclusions There were only minimal associations of DNA methylation with childhood and adolescent BMI. With the advancing age of the participants across childhood and adolescence, we observed increasing overlap with altered DNA methylation loci reported in association with adult BMI. These findings may be compatible with the hypothesis that DNA methylation differences are mostly a consequence rather than a cause of obesity.
  • Sundar, Isaac K.; Yin, Qiangzong; Baier, Brian S.; Yan, Li; Mazur, Witold; Li, Dongmei; Susiarjo, Martha; Rahman, Irfan (2017)
    Background: Epigenetics changes have been shown to be affected by cigarette smoking. Cigarette smoke (CS)-mediated DNA methylation can potentially affect several cellular and pathophysiological processes, acute exacerbations, and comorbidity in the lungs of patients with chronic obstructive pulmonary disease (COPD). We sought to determine whether genome-wide lung DNA methylation profiles of smokers and patients with COPD were significantly different from non-smokers. We isolated DNA from parenchymal lung tissues of patients including eight lifelong non-smokers, eight current smokers, and eight patients with COPD and analyzed the samples using Illumina's Infinium HumanMethylation450 BeadChip. Results: Our data revealed that the differentially methylated genes were related to top canonical pathways (e.g., G beta gamma signaling, mechanisms of cancer, and nNOS signaling in neurons), disease and disorders (organismal injury and abnormalities, cancer, and respiratory disease), and molecular and cellular functions (cell death and survival, cellular assembly and organization, cellular function and maintenance) in patients with COPD. The genome-wide DNA methylation analysis identified suggestive genes, such as NOS1AP, TNFAIP2, BID, GABRB1, ATXN7, and THOC7 with DNA methylation changes in COPD lung tissues that were further validated by pyrosequencing. Pyrosequencing validation confirmed hyper-methylation in smokers and patients with COPD as compared to non-smokers. However, we did not detect significant differences in DNA methylation for TNFAIP2, ATXN7, and THOC7 genes in smokers and COPD groups despite the changes observed in the genome-wide analysis. Conclusions: Our study suggests that DNA methylation in suggestive genes, such as NOS1AP, BID, and GABRB1 may be used as epigenetic signatures in smokers and patients with COPD if the same is validated in a larger cohort. Future studies are required to correlate DNA methylation status with transcriptomics of selective genes identified in this study and elucidate their role and involvement in the progression of COPD and its exacerbations.
  • Rounge, Trine B.; Page, Christian M.; Lepistö, Maija; Ellonen, Pekka; Andreassen, Bettina K.; Weiderpass, Elisabete (2016)
    Aim: We performed an epigenome-wide association study within the Finnish Health in Teens cohort to identify differential DNA methylation and its association with BMI in adolescents. Materials & methods: Differential DNA methylation analyses of 3.1 million CpG sites were performed in saliva samples from 50 lean and 50 heavy adolescent girls by genome-wide targeted bisulfite-sequencing. Results: We identified 100 CpG sites with p-values <0.000524, seven regions by 'bumphunting' and five CpG islands that differed significantly between the two groups. The ten CpG sites and regions most strongly associated with BMI substantially overlapped with obesity-and insulin-related genes, including MC2R, IGFBPL1, IP6K1 and IGF2BP1. Conclusion: Our findings suggest an association between the saliva methylome and BMI in adolescence.
  • Peltomäki, Paivi; Olkinuora, Alisa; Nieminen, Taina T. (2020)
    ABSTRACT Introduction Up to one third of colorectal cancers show familial clustering and 5% are hereditary single-gene disorders. Hereditary non-polyposis colorectal cancer comprises DNA mismatch repair-deficient and -proficient subsets, represented by Lynch syndrome (LS) and familial colorectal cancer type X (FCCTX), respectively. Accurate knowledge of molecular etiology and genotype-phenotype correlations are critical for tailored cancer prevention and treatment. Areas covered The authors highlight advances in the molecular dissection of hereditary non-polyposis colorectal cancer, based on recent literature retrieved from PubMed. Future possibilities for novel gene discoveries are discussed. Expert commentary LS is molecularly well established, but new information is accumulating of the associated clinical and tumor phenotypes. FCCTX remains poorly defined, but several promising candidate genes have been discovered and share some preferential biological pathways. Multi-level characterization of specimens from large patient cohorts representing multiple populations, combined with proper bioinformatic and functional analyses, will be necessary to resolve the outstanding questions.