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Epigenetic biomarkers: a step forward for understanding periodontitis
Anders M. Lindroth,박윤정 대한치주과학회 2013 Journal of Periodontal & Implant Science Vol.43 No.3
Periodontitis is a common oral disease that is characterized by infection and inflammation of the tooth supporting tissues. While its incidence is highly associated with outgrowth of the pathogenic microbiome, some patients show signs of predisposition and quickly fall into recurrence after treatment. Recent research using genetic associations of candidates as well as genome-wide analysis highlights that variations in genes related to the inflammatory response are associated with an increased risk of periodontitis. Intriguingly, some of the genes are regulated by epigenetic modifications, supposedly established and reprogrammed in response to environmental stimuli. In addition, the treatment with epigenetic drugs improves treatment of periodontitis in a mouse model. In this review, we highlight some of the recent progress identifying genetic factors associated with periodontitis and point to promising approaches in epigenetic research that may contribute to the understanding of molecular mechanisms involving different responses in individuals and the early detection of predispositions that may guide in future oral treatment and disease prevention.
PRC2 loss amplifies Ras signaling in cancer
Baude, Annika,Lindroth, Anders M,Plass, Christoph Nature Pub. Co 2014 Nature genetics Vol.46 No.11
The histone-modifying PRC2 complex has an ambiguous role in cancer, bearing both oncogenic and tumor-suppressive features depending on cell type. Studies of malignant peripheral nerve sheath tumors (MPNSTs) have now identified loss-of-function mutations altering PRC2 subunits, leading to the amplification of Ras-driven transcription and conferring vulnerability to BRD4 inhibitors.
Arab, K.,Park, Y.,Lindroth, Anders M.,Schafer, A.,Oakes, C.,Weichenhan, D.,Lukanova, A.,Lundin, E.,Risch, A.,Meister, M.,Dienemann, H.,Dyckhoff, G.,Herold-Mende, C.,Grummt, I.,Niehrs, C.,Plass, C. Cell Press 2014 Molecular cell Vol.55 No.4
DNA methylation is a dynamic and reversible process that governs gene expression during development and disease. Several examples of active DNA demethylation have been documented, involving genome-wide and gene-specific DNA demethylation. How demethylating enzymes are targeted to specific genomic loci remains largely unknown. We show that an antisense lncRNA, termed TARID (for TCF21 antisense RNA inducing demethylation), activates TCF21 expression by inducing promoter demethylation. TARID interacts with both the TCF21 promoter and GADD45A (growth arrest and DNA-damage-inducible, alpha), a regulator of DNA demethylation. GADD45A in turn recruits thymine-DNA glycosylase for base excision repair-mediated demethylation involving oxidation of 5-methylcytosine to 5-hydroxymethylcytosine in the TCF21 promoter by ten-eleven translocation methylcytosine dioxygenase proteins. The results reveal a function of lncRNAs, serving as a genomic address label for GADD45A-mediated demethylation of specific target genes.
Alterations in cardiac DNA methylation in human dilated cardiomyopathy
Haas, Jan,Frese, Karen S,Park, Yoon Jung,Keller, Andreas,Vogel, Britta,Lindroth, Anders M,Weichenhan, Dieter,Franke, Jennifer,Fischer, Simon,Bauer, Andrea,Marquart, Sabine,Sedaghat-Hamedani, Farbod,Ka WILEY-VCH Verlag 2013 EMBO molecular medicine Vol.5 No.3
<P>Dilated cardiomyopathies (DCM) show remarkable variability in their age of onset, phenotypic presentation, and clinical course. Hence, disease mechanisms must exist that modify the occurrence and progression of DCM, either by genetic or epigenetic factors that may interact with environmental stimuli. In the present study, we examined genome-wide cardiac DNA methylation in patients with idiopathic DCM and controls. We detected methylation differences in pathways related to heart disease, but also in genes with yet unknown function in DCM or heart failure, namely <I>Lymphocyte antigen 75</I> (<I>LY75</I>), <I>Tyrosine kinase-type cell surface receptor HER3</I> (<I>ERBB3</I>), <I>Homeobox B13</I> (<I>HOXB13</I>) and <I>Adenosine receptor A2A</I> (<I>ADORA2A</I>). Mass-spectrometric analysis and bisulphite-sequencing enabled confirmation of the observed DNA methylation changes in independent cohorts. Aberrant DNA methylation in DCM patients was associated with significant changes in <I>LY75</I> and <I>ADORA2A</I> mRNA expression, but not in <I>ERBB3</I> and <I>HOXB13</I>. <I>In vivo</I> studies of orthologous <I>ly75</I> and <I>adora2a</I> in zebrafish demonstrate a functional role of these genes in adaptive or maladaptive pathways in heart failure.</P>
Park, J H,Yoo, Y,Cho, M,Lim, J,Lindroth, A M,Park, Y J Nature Publishing Group 2018 International Journal of Obesity Vol.42 No.2
<P>CONCLUSION: Our findings demonstrate that male founder obesity influences impaired glucose regulation in F2 progeny possibly via ER stress in a sex-specific manner and it is, in part, contributed by altered DNA methylation at the Nr1h3 locus.</P>
Role of Angiogenin-mediated tRNA Fragmentation in Transmission of Diet-Induced Metabolic Stress
Eunbi Lee,Seo Yoon Choi,Jihye Park,Anders M. Lindroth,Yoon Jung Park 한국식품영양과학회 2021 한국식품영양과학회 학술대회발표집 Vol.2021 No.10
Epigenetic dysregulation has been suggested as one of the possible mechanisms by which parental metabolic stress is transmitted into the offspring. We investigated how the paternal diet stress was transmitted through male germline. Firstly, we analyzed differential metabolic pathway in sperms in response to high fat diet (HFD) using metabolome data. Aminoacyl-tRNA biosynthesis was upregulated in HFD group. Next, tRNA modification-related genes were investigated. Their expression levels were increased in testis by HFD. As known upregulated Angiogenin (Ang) expression induces tRNA fragmentation, we analyzed small RNAs in sperm using smRNA sequencing. The amount of 5" fragments were increased in HFD. Finally, activated mTOR pathway in testis were detected as an upstream regulator. We validated that mTOR activation with compound C increased Ang expression and subsequently tRNA fragmentation. Results from smRNA seq analysis showed a greater number of tRNA fragments in mTOR activating cells. In conclusion, our data suggested that chronic mTOR activity induction by diet stress led to upregulation of Ang-mediated tRNA fragmentation, which might be a key of transgenerational mechanism.
Yoo, Y,Park, J H,Weigel, C,Liesenfeld, D B,Weichenhan, D,Plass, C,Seo, D-G,Lindroth, A M,Park, Y J Nature Publishing Group 2017 International Journal of Obesity Vol.41 No.4
<P>CONCLUSIONS: TET proteins, particularly TET2, were required for adipogenesis by modulating DNA methylation at the Ppar. locus, subsequently by inducing Ppar. gene expression.</P>