scholarly journals Metastatic Paragangliomas and Pheochromocytomas: An Epigenetic View

2021 ◽  
Author(s):  
María-Dolores Chiara ◽  
Lucía Celada ◽  
Andrés San José Martinez ◽  
Tamara Cubiella ◽  
Enol Álvarez-González ◽  
...  
Keyword(s):  
Histone Modification ◽  
Succinate Dehydrogenase ◽  
Protein Complex ◽  
Histone Demethylases ◽  
Epigenetic Landscape ◽  
Metastatic Cascade ◽  
Genes Encoding ◽  
Hereditary Tumors ◽  
Non Coding Rnas ◽  
Histone Modification Enzymes

Paragangliomas and pheochromocytoma (PPGLs) are hereditary tumors in about 40% of cases. Mutations in the genes encoding for components of the mitochondrial succinate dehydrogenase protein complex (SDHB, SDHD, SDHC) are among the most prevalent. Most PPGLs have a benign behavior, but patients with germline SDHB mutations may develop metastatic PPGLs in up to 30% of cases. This suggest that the SDH substrate, succinate, is key for the activation of the metastatic cascade. The last decade has witnessed significant advances in our understanding of how succinate may have oncogenic properties. It is now widely accepted that succinate is an oncometabolite that modifies the epigenetic landscape of SDH-deficient tumors via modulating the activities of DNA and histone modification enzymes. In this chapter, we summarize recent discoveries linking SDH-deficiency and metastasis in SDH-deficient PPGLs via inhibition of DNA methylcytosine dioxygenases, histone demethylases and modified expression of non-coding RNAs. We also highlight promising therapeutic avenues that may be used to counteract epigenetic deregulations.

scholarly journals Diagnostic Investigation of Lesions Associated with Succinate Dehydrogenase Defects

2018 ◽  
Vol 51 (07) ◽  
pp. 414-418
Author(s):  
David Taïeb ◽  
Henri Timmers ◽  
Karel Pacak
Keyword(s):  
Tumor Suppressor ◽  
Succinate Dehydrogenase ◽  
Protein Function ◽  
Complete Loss ◽  
Diverse Group ◽  
Mitochondrial Enzyme ◽  
Diagnostic Investigation ◽  
Genes Encoding ◽  
Hereditary Tumors

AbstractThe mitochondrial enzyme succinate dehydrogenase (SDH) acts as a tumor suppressor. Biallelic inactivation of one of the genes encoding for SDH subunits (collectively named SDHx) leads to complete loss of the protein function and the development of diverse group of tumors. Pheochromocytomas-paragangliomas are the prime example of hereditary tumors caused by SDH deficiency. In this review, we discuss the roles of imaging examinations, and illustrate new insights into genotype-imaging phenotype relationships.

Abstract 17382: Jumonji-C Histone Demethylases Are Cellular Iron Sensors That Control mTORC1 and Mitophagy

Circulation ◽  
2018 ◽  
Vol 138 (Suppl_1) ◽  
Author(s):  
Jason S Shapiro ◽  
Hsiang-Chun Chang ◽  
Hossein Ardehali
Keyword(s):  
Mitochondrial Dynamics ◽  
Rna Stability ◽  
Cellular Growth ◽  
Histone Demethylases ◽  
Epigenetic Landscape ◽  
Selective Autophagy ◽  
Cellular Iron ◽  
Essential Nutrient ◽  
Amino Acid Homeostasis ◽  
Mtor Activity

Iron is an essential nutrient and is critical for cellular growth and metabolism. Here, we delineate a novel mechanism by which iron alters amino acid homeostasis and mTOR activity by remodeling the cellular epigenetic landscape. We find that iron deficiency inactivates Jumonji-C domain containing histone-demethylases, resulting in histone hyper-methylation and silencing of the leucine transporter LAT3 and obligatory mTORC1 cofactor RAPTOR. Additionally, we identify that mTOR-mediated regulation of RNA stability through tristetraprolin (TTP) is a novel and requisite step in selective-autophagy. In the absence of TTP, mitochondria damaged by the loss of iron cannot undergo fission, rendering the mitochondria too large for engulfment and subsequent recycling. Accumulation of damaged mitochondria leads to defective oxidative metabolism and impairs hepatic gluconeogenesis in response to fasting. These studies uncover a novel pathway that integrates iron sensing with cellular metabolism, mitochondrial dynamics and autophagy.

scholarly journals Genetic and Epigenetic Aspects of Atopic Dermatitis

2020 ◽  
Vol 21 (18) ◽  
pp. 6484 ◽  
Author(s):  
Bogusław Nedoszytko ◽  
Edyta Reszka ◽  
Danuta Gutowska-Owsiak ◽  
Magdalena Trzeciak ◽  
Magdalena Lange ◽  
...  
Keyword(s):  
Atopic Dermatitis ◽  
Treatment Strategies ◽  
Structural Proteins ◽  
Epigenetic Changes ◽  
Epigenetic Alterations ◽  
Adaptive Immune ◽  
Genes Encoding ◽  
Inflammatory Processes ◽  
Non Coding Rnas

Atopic dermatitis is a heterogeneous disease, in which the pathogenesis is associated with mutations in genes encoding epidermal structural proteins, barrier enzymes, and their inhibitors; the role of genes regulating innate and adaptive immune responses and environmental factors inducing the disease is also noted. Recent studies point to the key role of epigenetic changes in the development of the disease. Epigenetic modifications are mainly mediated by DNA methylation, histone acetylation, and the action of specific non-coding RNAs. It has been documented that the profile of epigenetic changes in patients with atopic dermatitis (AD) differs from that observed in healthy people. This applies to the genes affecting the regulation of immune response and inflammatory processes, e.g., both affecting Th1 bias and promoting Th2 responses and the genes of innate immunity, as well as those encoding the structural proteins of the epidermis. Understanding of the epigenetic alterations is therefore pivotal to both create new molecular classifications of atopic dermatitis and to enable the development of personalized treatment strategies.

scholarly journals Defining the epigenetic status of blood cells using a cyanine-based fluorescent probe for PRMT1

2018 ◽  
Vol 2 (21) ◽  
pp. 2829-2836
Author(s):  
Hairui Su ◽  
Chiao-Wang Sun ◽  
Szu-Mam Liu ◽  
Xin He ◽  
Hao Hu ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Histone Modification ◽  
Near Infrared ◽  
Lymphocyte Activation ◽  
Staining Intensity ◽  
Mouse Bone Marrow ◽  
Dynamic Regulation ◽  
Hematopoietic Stem ◽  
Negative Effect ◽  
Histone Modification Enzymes

Abstract Dynamic regulation of histone modification enzymes such as PRMT1 (protein arginine methyltransferase 1) determines the ordered epigenetic transitions in hematopoiesis. Sorting cells according to the expression levels of histone modification enzymes may further define subpopulations in hematopoietic lineages with unique differentiation potentials that are presently defined by surface markers. We discovered a vital near infrared dye, E84, that fluoresces brightly following binding to PRMT1 and excitation with a red laser. The staining intensity as measured by flow cytometry is correlated with the PRMT1 expression level. Importantly, E84 staining has no apparent negative effect on the proliferation of the labeled cells. Given that long-term hematopoietic stem cells (LT-HSCs) produce low levels of PRMT1, we used E84 to sort LT-HSCs from mouse bone marrow. We found that SLAM (the signalling lymphocyte activation molecule family) marker–positive LT-HSCs were enriched in the E84low cell fraction. We then performed bone marrow transplantations with E84high or E84low Lin−Sca1+Kit+ (LSK) cells and showed that whole blood cell lineages were successfully reconstituted 16 weeks after transplanting 200 E84low LSK cells. Thus, E84 is a useful new tool to probe the role of PRMT1 in hematopoiesis and leukemogenesis. Developing E84 and other small molecules to label histone modification enzymes provides a convenient approach without modifying gene loci to study the interaction between hematopoietic stem/progenitor cell epigenetic status and differentiation state.

scholarly journals Cell-Based Mechanosensation, Epigenetics, and Non-Coding RNAs in Progression of Cardiac Fibrosis

2019 ◽  
Vol 21 (1) ◽  
pp. 28 ◽  
Author(s):  
Silvia Ferrari ◽  
Maurizio Pesce
Keyword(s):  
Stromal Cells ◽  
Cardiac Fibrosis ◽  
Cardiac Fibroblasts ◽  
Normal Function ◽  
Epigenetic Landscape ◽  
Present Contribution ◽  
Myocardial Wall ◽  
Non Coding Rna ◽  
Rna Biology ◽  
Non Coding Rnas

The heart is par excellence the ‘in-motion’ organ in the human body. Compelling evidence shows that, besides generating forces to ensure continuous blood supply (e.g., myocardial contractility) or withstanding passive forces generated by flow (e.g., shear stress on endocardium, myocardial wall strain, and compression strain at the level of cardiac valves), cells resident in the heart respond to mechanical cues with the activation of mechanically dependent molecular pathways. Cardiac stromal cells, most commonly named cardiac fibroblasts, are central in the pathologic evolution of the cardiovascular system. In their normal function, these cells translate mechanical cues into signals that are necessary to renew the tissues, e.g., by continuously rebuilding the extracellular matrix being subjected to mechanical stress. In the presence of tissue insults (e.g., ischemia), inflammatory cues, or modifiable/unmodifiable risk conditions, these mechanical signals may be ‘misinterpreted’ by cardiac fibroblasts, giving rise to pathology programming. In fact, these cells are subject to changing their phenotype from that of matrix renewing to that of matrix scarring cells—the so-called myo-fibroblasts—involved in cardiac fibrosis. The links between alterations in the abilities of cardiac fibroblasts to ‘sense’ mechanical cues and molecular pathology programming are still under investigation. On the other hand, various evidence suggests that cell mechanics may control stromal cells phenotype by modifying the epigenetic landscape, and this involves specific non-coding RNAs. In the present contribution, we will provide examples in support of this more integrated vision of cardiac fibrotic progression based on the decryption of mechanical cues in the context of epigenetic and non-coding RNA biology.

scholarly journals Metabolic Diseases Downregulate the Majority of Histone Modification Enzymes, Making a Few Upregulated Enzymes Novel Therapeutic Targets—“Sand Out and Gold Stays”

2016 ◽  
Vol 9 (1) ◽  
pp. 49-66 ◽  
Author(s):  
Ying Shao ◽  
Valeria Chernaya ◽  
Candice Johnson ◽  
William Y. Yang ◽  
Ramon Cueto ◽  
...  
Keyword(s):  
Histone Modification ◽  
Metabolic Diseases ◽  
Therapeutic Targets ◽  
Histone Modification Enzymes ◽  
Novel Therapeutic

scholarly journals The Roles of Epigenetics Regulation in Bone Metabolism and Osteoporosis

2021 ◽  
Vol 8 ◽  
Author(s):  
Fei Xu ◽  
Wenhui Li ◽  
Xiao Yang ◽  
Lixin Na ◽  
Linjun Chen ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Histone Modification ◽  
Osteogenic Differentiation ◽  
Bone Metabolism ◽  
Bone Fragility ◽  
Research Progress ◽  
Epigenetic Mechanisms ◽  
Mineral Density ◽  
Transcriptional Regulatory ◽  
Non Coding Rnas

Osteoporosis is a metabolic disease characterized by decreased bone mineral density and the destruction of bone microstructure, which can lead to increased bone fragility and risk of fracture. In recent years, with the deepening of the research on the pathological mechanism of osteoporosis, the research on epigenetics has made significant progress. Epigenetics refers to changes in gene expression levels that are not caused by changes in gene sequences, mainly including DNA methylation, histone modification, and non-coding RNAs (lncRNA, microRNA, and circRNA). Epigenetics play mainly a post-transcriptional regulatory role and have important functions in the biological signal regulatory network. Studies have shown that epigenetic mechanisms are closely related to osteogenic differentiation, osteogenesis, bone remodeling and other bone metabolism-related processes. Abnormal epigenetic regulation can lead to a series of bone metabolism-related diseases, such as osteoporosis. Considering the important role of epigenetic mechanisms in the regulation of bone metabolism, we mainly review the research progress on epigenetic mechanisms (DNA methylation, histone modification, and non-coding RNAs) in the osteogenic differentiation and the pathogenesis of osteoporosis to provide a new direction for the treatment of bone metabolism-related diseases.

scholarly journals Regulation of CHD2 expression by the Chaserr long noncoding RNA is essential for viability

2019 ◽  
Author(s):  
Aviv Rom ◽  
Liliya Melamed ◽  
Micah Jonathan Goldrich ◽  
Rotem Kadir ◽  
Matan Golan ◽  
...  
Keyword(s):  
Noncoding Rna ◽  
Transcription Start ◽  
Chromatin Remodelers ◽  
Neurodevelopmental Delay ◽  
Protein Levels ◽  
Damage Response ◽  
Genes Encoding ◽  
Highly Expressed Genes ◽  
Non Coding Rnas ◽  
Severe Growth

AbstractGenomic loci adjacent to genes encoding for transcription factors and chromatin remodelers are enriched for long non-coding RNAs (lncRNAs), but the functional importance of this enrichment is largely unclear. Chromodomain helicase DNA binding protein 2 (Chd2) is a chromatin remodeller with various reported functions in cell differentiation and DNA damage response. Heterozygous mutations in human CHD2 have been implicated in epilepsy, neurodevelopmental delay, and intellectual disability. Here we show that Chaserr, a highly conserved lncRNA transcribed from a region near the transcription start site of Chd2 and on the same strand, acts in concert with the CHD2 protein to maintain proper Chd2 expression levels. Loss of Chaserr in mice leads to early postnatal lethality in homozygous mice, and severe growth retardation in heterozygotes. Mechanistically, loss of Chaserr leads to substantially increased Chd2 mRNA and protein levels, which in turn lead to increased transcriptional interference by inhibiting promoters found downstream of highly expressed genes. We further show that Chaserr production represses Chd2 expression solely in cis, and that the phenotypic consequences of Chaserr loss are rescued when Chd2 is perturbed as well. Targeting Chaserr is thus a potentially viable strategy for increasing CHD2 levels in haploinsufficient individuals.

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