scholarly journals Altered DNA methylation in kidney disease: useful markers and therapeutic targets

2022 ◽  
Author(s):  
Kaori Hayashi
Keyword(s):  
Dna Methylation ◽  
Dna Damage ◽  
Dna Repair ◽  
Kidney Disease ◽  
Environmental Changes ◽  
Therapeutic Targets ◽  
Epigenetic Mechanism ◽  
Epigenetic Changes ◽  
Epigenetic Alterations ◽  
Lifestyle Related Diseases

AbstractRecent studies have demonstrated the association of altered epigenomes with lifestyle-related diseases. Epigenetic regulation promotes biological plasticity in response to environmental changes, and such plasticity may cause a ‘memory effect’, a sustained effect of transient treatment or an insult in the course of lifestyle-related diseases. We investigated the significance of epigenetic changes in several genes required for renal integrity, including the nephrin gene in podocytes, and the sustained anti-proteinuric effect, focusing on the transcription factor Krüppel-like factor 4 (KLF4). We further reported the role of the DNA repair factor lysine-acetyl transferase 5 (KAT5), which acts coordinately with KLF4, in podocyte injury caused by a hyperglycemic state through the acceleration of DNA damage and epigenetic alteration. In contrast, KAT5 in proximal tubular cells prevents acute kidney injury via glomerular filtration regulation by an epigenetic mechanism as well as promotion of DNA repair, indicating the cell type-specific action and roles of DNA repair factors. This review summarizes epigenetic alterations in kidney diseases, especially DNA methylation, and their utility as markers and potential therapeutic targets. Focusing on transcription factors or DNA damage repair factors associated with epigenetic changes may be meaningful due to their cell-specific expression or action. We believe that a better understanding of epigenetic alterations in the kidney will lead to the development of a novel strategy for chronic kidney disease (CKD) treatment.

scholarly journals Epigenetics of Meningiomas

2015 ◽  
Vol 2015 ◽  
pp. 1-6 ◽  
Author(s):  
Balázs Murnyák ◽  
László Bognár ◽  
Álmos Klekner ◽  
Tibor Hortobágyi
Keyword(s):  
Dna Methylation ◽  
Central Nervous System ◽  
Genetic Alterations ◽  
Chromatin Modifications ◽  
Epigenetic Changes ◽  
Epigenetic Alterations ◽  
Central Nervous System Tumours ◽  
Growing Body ◽  
Tumour Initiation ◽  
Reversible Nature

Meningiomas account for one-third of all adult central nervous system tumours and are divided into three WHO grades. In contrast to the relatively well characterized genetic alterations, our current understanding of epigenetic modifications involved in the meningioma-genesis and progression is rather incomplete. Contrary to genetic alterations, epigenetic changes do not alter the primary DNA sequence and their reversible nature serves as an excellent basis for prevention and development of novel personalised tumour therapies. Indeed, growing body of evidence suggests that disturbed epigenetic regulation plays a key role in the pathogenesis of meningiomas. Altered DNA methylation, microRNA expression, histone, and chromatin modifications are frequently noted in meningiomas bearing prognostic and therapeutic relevance. In this review we provide an overview on recently identified epigenetic alterations in meningiomas and discuss their role in tumour initiation, progression, and recurrence.

scholarly journals Epigenetic Alterations in Podocytes in Diabetic Nephropathy

2021 ◽  
Vol 12 ◽  
Author(s):  
Erina Sugita ◽  
Kaori Hayashi ◽  
Akihito Hishikawa ◽  
Hiroshi Itoh
Keyword(s):  
Dna Damage ◽  
Diabetic Nephropathy ◽  
Epigenetic Changes ◽  
Epigenetic Alterations ◽  
Human Samples ◽  
Differentiated Cells ◽  
Damage Repair ◽  
Patients With Diabetes ◽  
Stage Renal Disease ◽  
End Stage

Recently, epigenetic alterations have been shown to be involved in the pathogenesis of diabetes and its complications. Kidney podocytes, which are glomerular epithelial cells, are important cells that form a slit membrane—a barrier for proteinuria. Podocytes are terminally differentiated cells without cell division or replenishment abilities. Therefore, podocyte damage is suggested to be one of the key factors determining renal prognosis. Recent studies, including ours, suggest that epigenetic changes in podocytes are associated with chronic kidney disease, including diabetic nephropathy. Furthermore, the association between DNA damage repair and epigenetic changes in diabetic podocytes has been demonstrated. Detection of podocyte DNA damage and epigenetic changes using human samples, such as kidney biopsy and urine-derived cells, may be a promising strategy for estimating kidney damage and renal prognoses in patients with diabetes. Targeting epigenetic podocyte changes and associated DNA damage may become a novel therapeutic strategy for preventing progression to end-stage renal disease (ESRD) and provide a possible prognostic marker in diabetic nephropathy. This review summarizes recent advances regarding epigenetic changes, especially DNA methylation, in podocytes in diabetic nephropathy and addresses detection of these alterations in human samples. Additionally, we focused on DNA damage, which is increased under high-glucose conditions and associated with the generation of epigenetic changes in podocytes. Furthermore, epigenetic memory in diabetes is discussed. Understanding the role of epigenetic changes in podocytes in diabetic nephropathy may be of great importance considering the increasing diabetic nephropathy patient population in an aging society.

scholarly journals DNA Methylation of PI3K/AKT Pathway-Related Genes Predicts Outcome in Patients with Pancreatic Cancer: A Comprehensive Bioinformatics-Based Study

Cancers ◽  
2021 ◽  
Vol 13 (24) ◽  
pp. 6354
Author(s):  
Inês Faleiro ◽  
Vânia Palma Roberto ◽  
Secil Demirkol Canli ◽  
Nicolas A. Fraunhoffer ◽  
Juan Iovanna ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Dna Methylation ◽  
Methylation Status ◽  
Therapeutic Targets ◽  
The Cancer Genome Atlas ◽  
Prognostic Indicators ◽  
Diagnostic Tools ◽  
Akt Pathway ◽  
Epigenetic Alterations ◽  
Epigenetic Biomarkers

Pancreatic cancer (PCA) is one of the most lethal malignancies worldwide with a 5-year survival rate of 9%. Despite the advances in the field, the need for an earlier detection and effective therapies is paramount. PCA high heterogeneity suggests that epigenetic alterations play a key role in tumour development. However, only few epigenetic biomarkers or therapeutic targets have been identified so far. Here we explored the potential of distinct DNA methylation signatures as biomarkers for early detection and prognosis of PCA. PI3K/AKT-related genes differentially expressed in PCA were identified using the Pancreatic Expression Database (n = 153). Methylation data from PCA patients was obtained from The Cancer Genome Atlas (n = 183), crossed with clinical data to evaluate the biomarker potential of the epigenetic signatures identified and validated in independent cohorts. The majority of selected genes presented higher expression and hypomethylation in tumour tissue. The methylation signatures of specific genes in the PI3K/AKT pathway could distinguish normal from malignant tissue at initial disease stages with AUC > 0.8, revealing their potential as PCA diagnostic tools. ITGA4, SFN, ITGA2, and PIK3R1 methylation levels could be independent prognostic indicators of patients’ survival. Methylation status of SFN and PIK3R1 were also associated with disease recurrence. Our study reveals that the methylation levels of PIK3/AKT genes involved in PCA could be used to diagnose and predict patients’ clinical outcome with high sensitivity and specificity. These results provide new evidence of the potential of epigenetic alterations as biomarkers for disease screening and management and highlight possible therapeutic targets.

scholarly journals DNA damage activates mTORC1 signaling in podocytes leading to glomerulosclerosis

2020 ◽  
Author(s):  
Fabian Braun ◽  
Linda Blomberg ◽  
Roman Akbar-Haase ◽  
Victor G. Puelles ◽  
Milagros N. Wong ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Repair ◽  
Kidney Disease ◽  
Excision Repair ◽  
Repair Gene ◽  
Glomerular Diseases ◽  
Genomic Stress ◽  
Dna Repair Gene ◽  
Mtorc1 Signaling

AbstractDNA repair is essential for preserving genome integrity and ensures cellular functionality and survival. Podocytes have a very limited regenerative capacity, and their survival is essential to maintain kidney function. While podocyte depletion is a hallmark of glomerular diseases, the mechanisms leading to severe podocyte injury and loss remain largely unclear. We detected perturbations in DNA repair in biopsies from patients with various podocyte-related glomerular diseases and identified single-nucleotide polymorphisms associated with the expression of DNA repair genes in patients suffering from proteinuric kidney disease. Genome maintenance through nucleotide excision repair (NER) proved to be indispensable for podocyte homeostasis. Podocyte-specific knockout of the NER endonuclease co-factor Ercc1 resulted in accumulation of DNA damage, proteinuria, podocyte loss and glomerulosclerosis. The response to this genomic stress was fundamentally different to other cell types, as podocytes activate mTORC1 signaling upon DNA damage in vitro and in vivo.Visual AbstractSchematic overview of main findings – Accumulation of genomic stress in podocytes occurs through endogenous or exogenous agents as well as genetic factors causing decreased DNA repair gene expression. Excessive DNA damage leads to the activation of mTORC1 triggering podocyte effacement, loss, glomerular scarring and proteinuric kidney disease.

scholarly journals The novel gene LRP15 is regulated by DNA methylation and confers increased efficiency of DNA repair of ultraviolet-induced DNA damage

BMB Reports ◽  
2008 ◽  
Vol 41 (3) ◽  
pp. 230-235 ◽  
Author(s):  
Zhou-Min Xu ◽  
Wei-Ran Gao ◽  
Qi Mei ◽  
Jian Chen ◽  
Jing Lu
Keyword(s):  
Dna Methylation ◽  
Dna Damage ◽  
Dna Repair ◽  
The Novel ◽  
Novel Gene

scholarly journals DNA Damage Repair and DNA Methylation in the Kidney

2019 ◽  
Vol 50 (2) ◽  
pp. 81-91 ◽  
Author(s):  
Kaori Hayashi ◽  
Akihito Hishikawa ◽  
Hiroshi Itoh
Keyword(s):  
Dna Methylation ◽  
Dna Damage ◽  
Dna Repair ◽  
Methylation Status ◽  
Dna Damage Repair ◽  
Strand Break ◽  
Repair System ◽  
Damage Repair ◽  
Dna Double Strand Break ◽  
Cell Type Specific

The DNA repair system is essential for the maintenance of genome integrity and is mainly investigated in the areas of aging and cancer. The DNA repair system is strikingly cell-type specific, depending on the expression of DNA repair factors; therefore, different DNA repair systems may exist in each type of kidney cell. Importance of DNA repair in the kidney is suggested by renal phenotypes caused by both genetic mutations in the DNA repair pathway and increased stimuli of DNA damage. Recently, we reported the importance of DNA double-strand break repair in glomerular podocytes and its involvement in the alteration of DNA methylation status, which regulates podocyte phenotypes. In this review, we summarize the roles of the DNA repair system in the kidneys and possible associations with altered kidney DNA methylation, which have been infrequently reported together. Investigations of DNA damage repair and epigenetic changes in the kidneys may achieve a profound understanding of kidney aging and diseases.

scholarly journals Gene duplication, rather than epigenetic changes, drives FGF4 overexpression in KIT/PDGFRA/SDH/RAS-P WT GIST

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Milena Urbini ◽  
Annalisa Astolfi ◽  
Valentina Indio ◽  
Margherita Nannini ◽  
Angela Schipani ◽  
...  
Keyword(s):  
Therapeutic Target ◽  
Molecular Mechanisms ◽  
Genomic Structure ◽  
Epigenetic Mechanism ◽  
Epigenetic Changes ◽  
Epigenetic Alterations ◽  
Wild Type ◽  
Gastrointestinal Stromal Tumours ◽  
Super Enhancer ◽  
First Time

AbstractGastrointestinal stromal tumours that are wild type for KIT and PDGFRA are referred to as WT GISTs. Of these tumours, SDH-deficient (characterized by the loss of SDHB) and quadruple WT GIST (KIT/PDGFRA/SDH/RAS-P WT) subgroups were reported to display a marked overexpression of FGF4, identifying a putative common therapeutic target for the first time. In SDH-deficient GISTs, methylation of an FGF insulator region was found to be responsible for the induction of FGF4 expression. In quadruple WT, recurrent focal duplication of FGF3/FGF4 was reported; however, how it induced FGF4 expression was not investigated. To assess whether overexpression of FGF4 in quadruple WT could be driven by similar epigenetic mechanisms as in SDH-deficient GISTs, we performed global and locus-specific (on FGF4 and FGF insulator) methylation analyses. However, no epigenetic alterations were detected. Conversely, we demonstrated that in quadruple WT GISTs, FGF4 expression and the structure of the duplication were intimately connected, with the copy of FGF4 closer to the ANO1 super-enhancer being preferentially expressed. In conclusion, we demonstrated that in quadruple WT GISTs, FGF4 overexpression is not due to an epigenetic mechanism but rather to the specific genomic structure of the duplication. Even if FGF4 overexpression is driven by different molecular mechanisms, these findings support an increasing biologic relevance of the FGFR pathway in WT GISTs, both in SDH-deficient and quadruple WT GISTs, suggesting that it may be a common therapeutic target.

scholarly journals DNA Methylation Dynamics in Atlantic Salmon (Salmo salar) Challenged With High Temperature and Moderate Hypoxia

2021 ◽  
Vol 7 ◽  
Author(s):  
Anne Beemelmanns ◽  
Laia Ribas ◽  
Dafni Anastasiadi ◽  
Javier Moraleda-Prados ◽  
Fábio S. Zanuzzo ◽  
...  
Keyword(s):  
Dna Methylation ◽  
High Temperature ◽  
Atlantic Salmon ◽  
Salmo Salar ◽  
Environmental Changes ◽  
Regulatory Elements ◽  
Cpg Methylation ◽  
Epigenetic Mechanism ◽  
Moderate Hypoxia ◽  
Hypoxia Exposure

The marine environment is predicted to become warmer and more hypoxic, and these conditions may become a challenge for marine fish species. Phenotypically plastic responses facilitating acclimatization to changing environments can be mediated by DNA methylation through the modulation of gene expression. To investigate whether temperature and hypoxia exposure induce DNA methylation changes, we challenged post-smolt Atlantic salmon (Salmo salar) to increasing temperatures (12 → 20°C, 1°C week–1) under normoxia or moderate hypoxia (∼70% air saturation) and compared responses in the liver after 3 days or 4 weeks at 20°C. DNA methylation was studied in six genes related to temperature stress (cirbp, serpinh1), oxidative stress (prdx6, ucp2), apoptosis (jund), and metabolism (pdk3). Here, we report that exposure to high temperature, alone or combined with hypoxia, affected the methylation of CpG sites within different genomic regulatory elements around the transcription start of these temperature/hypoxia biomarker genes. Yet, we uncovered distinct CpG methylation profiles for each treatment group, indicating that each environmental condition may induce different epigenetic signatures. These CpG methylation responses were strongly dependent on the duration of stress exposure, and we found reversible, but also persistent, CpG methylation changes after 4 weeks of exposure to 20°C. Further, several of these changes in CpG methylation correlated with transcriptional changes, and thus, can be considered as regulatory epigenetic marks (epimarkers). Our study provides insights into the dynamic associations between CpG methylation and transcript expression in Atlantic salmon, and suggests that this epigenetic mechanism may mediate physiological acclimation to short-term and long-term environmental changes.

scholarly journals Epigenetic Changes Induced by Maternal Factors during Fetal Life: Implication for Type 1 Diabetes

Genes ◽  
2021 ◽  
Vol 12 (6) ◽  
pp. 887
Author(s):  
Ilaria Barchetta ◽  
Jeanette Arvastsson ◽  
Luis Sarmiento ◽  
Corrado M. Cilio
Keyword(s):  
Dna Methylation ◽  
Type 1 Diabetes ◽  
Environmental Factors ◽  
Autoimmune Diseases ◽  
Epigenetic Mechanism ◽  
Fetal Life ◽  
Epigenetic Changes ◽  
Maternal Factors ◽  
Immune Mediated

Organ-specific autoimmune diseases, such as type 1 diabetes, are believed to result from T-cell-mediated damage of the target tissue. The immune-mediated tissue injury, in turn, is known to depend on complex interactions between genetic and environmental factors. Nevertheless, the mechanisms whereby environmental factors contribute to the pathogenesis of autoimmune diseases remain elusive and represent a major untapped target to develop novel strategies for disease prevention. Given the impact of the early environment on the developing immune system, epigenetic changes induced by maternal factors during fetal life have been linked to a likelihood of developing an autoimmune disease later in life. In humans, DNA methylation is the epigenetic mechanism most extensively investigated. This review provides an overview of the critical role of DNA methylation changes induced by prenatal maternal conditions contributing to the increased risk of immune-mediated diseases on the offspring, with a particular focus on T1D. A deeper understanding of epigenetic alterations induced by environmental stressors during fetal life may be pivotal for developing targeted prevention strategies of type 1 diabetes by modifying the maternal environment.

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