O-GlcNAcylation and chromatin remodeling in mammals: an up-to-date overview

2017 ◽  
Vol 45 (2) ◽  
pp. 323-338 ◽  
Author(s):  
Maïté Leturcq ◽  
Tony Lefebvre ◽  
Anne-Sophie Vercoutter-Edouart
Keyword(s):  
Chromatin Remodeling ◽  
Dna Demethylation ◽  
Post Translational Modifications ◽  
Cellular Models ◽  
Active Dna Demethylation ◽  
Chromatin Regulators ◽  
Lysine Specific Demethylase ◽  
The Stability ◽  
Glcnac Transferase

Post-translational modifications of histones and the dynamic DNA methylation cycle are finely regulated by a myriad of chromatin-binding factors and chromatin-modifying enzymes. Epigenetic modifications ensure local changes in the architecture of chromatin, thus controlling in fine the accessibility of the machinery of transcription, replication or DNA repair to the chromatin. Over the past decade, the nutrient-sensor enzyme O-GlcNAc transferase (OGT) has emerged as a modulator of chromatin remodeling. In mammals, OGT acts either directly through dynamic and reversible O-GlcNAcylation of histones and chromatin effectors, or in an indirect manner through its recruitment into chromatin-bound multiprotein complexes. In particular, there is an increasing amount of evidence of a cross-talk between OGT and the DNA dioxygenase ten–eleven translocation proteins that catalyze active DNA demethylation. Conversely, the stability of OGT itself can be controlled by the histone lysine-specific demethylase 2 (LSD2). Finally, a few studies have explored the role of O-GlcNAcase (OGA) in chromatin remodeling. In this review, we summarize the recent findings on the link between OGT, OGA and chromatin regulators in mammalian cellular models, and discuss their relevance in physiological and pathological conditions.

scholarly journals SIZ1-mediated SUMOylation of ROS1 Enhances Its Stability and Positively Regulates Active DNA Demethylation in Arabidopsis

2020 ◽  
Author(s):  
Xiangfeng Kong ◽  
Yechun Hong ◽  
Yi-Feng Hsu ◽  
Huan Huang ◽  
Xue Liu ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Dna Demethylation ◽  
Dna Glycosylase ◽  
Wild Type ◽  
Dna Hypermethylation ◽  
Post Translational Modifications ◽  
Active Dna Demethylation ◽  
Short Summary ◽  
The Stability ◽  
Genomic Regions

AbstractThe 5-methylcytosine DNA glycosylase/lyase REPRESSOR OF SILENCING 1 (ROS1)-mediated active DNA demethylation is critical for shaping the genomic DNA methylation landscape in Arabidopsis. Whether and how the stability of ROS1 may be regulated by post-translational modifications is unknown. Using a methylation-sensitive PCR (CHOP-PCR)-based forward genetic screen for Arabidopsis DNA hypermethylation mutants, we identified the SUMO E3 ligase SIZ1 as a critical regulator of active DNA demethylation. Dysfunction of SIZ1 leads to hyper-methylation at approximately one thousand genomic regions. SIZ1 physically interacts with ROS1 and mediates the SUMOylation of ROS1. The SUMOylation of ROS1 is reduced in siz1 mutant plants. Compared to that in wild type plants, the protein level of ROS1 is significantly decreased, even though there is an increased level of ROS1 transcripts in siz1 mutant plants. Our results suggest that SIZ1 positively regulates active DNA demethylation by promoting the stability of ROS1 protein through SUMOylation.Short SummaryThe 5-methylcytosine DNA glycosylase/lyase REPRESSOR OF SILENCING 1 (ROS1) is indispensable for proper DNA methylation landscape in Arabidopsis. Whether and how the stability of ROS1 may be regulated by post-translational modifications is unknown. Here, we show that SIZ1-mediated SUMOylation of ROS1 enhances its stability and positively regulates active DNA demethylation.

scholarly journals FOXO1 mitigates the SMAD3/FOXL2C134W transcriptomic effect in a model of human adult granulosa cell tumor

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Christian Secchi ◽  
Paola Benaglio ◽  
Francesca Mulas ◽  
Martina Belli ◽  
Dwayne Stupack ◽  
...  
Keyword(s):  
Granulosa Cell ◽  
Chromatin Remodeling ◽  
Granulosa Cell Tumor ◽  
Cell Tumor ◽  
Rna Seq ◽  
Pathogenic Role ◽  
Rare Type ◽  
Cellular Models ◽  
Genome Wide

Abstract Background Adult granulosa cell tumor (aGCT) is a rare type of stromal cell malignant cancer of the ovary characterized by elevated estrogen levels. aGCTs ubiquitously harbor a somatic mutation in FOXL2 gene, Cys134Trp (c.402C < G); however, the general molecular effect of this mutation and its putative pathogenic role in aGCT tumorigenesis is not completely understood. We previously studied the role of FOXL2C134W, its partner SMAD3 and its antagonist FOXO1 in cellular models of aGCT. Methods In this work, seeking more comprehensive profiling of FOXL2C134W transcriptomic effects, we performed an RNA-seq analysis comparing the effect of FOXL2WT/SMAD3 and FOXL2C134W/SMAD3 overexpression in an established human GC line (HGrC1), which is not luteinized, and bears normal alleles of FOXL2. Results Our data shows that FOXL2C134W/SMAD3 overexpression alters the expression of 717 genes. These genes include known and novel FOXL2 targets (TGFB2, SMARCA4, HSPG2, MKI67, NFKBIA) and are enriched for neoplastic pathways (Proteoglycans in Cancer, Chromatin remodeling, Apoptosis, Tissue Morphogenesis, Tyrosine Kinase Receptors). We additionally expressed the FOXL2 antagonistic Forkhead protein, FOXO1. Surprisingly, overexpression of FOXO1 mitigated 40% of the altered genome-wide effects specifically related to FOXL2C134W, suggesting it can be a new target for aGCT treatment. Conclusions Our transcriptomic data provide novel insights into potential genes (FOXO1 regulated) that could be used as biomarkers of efficacy in aGCT patients.

RegulatING chromatin regulators: post-translational modification of the ING family of epigenetic regulators

2013 ◽  
Vol 450 (3) ◽  
pp. 433-442 ◽  
Author(s):  
Shankha Satpathy ◽  
Arash Nabbi ◽  
Karl Riabowol
Keyword(s):  
Biological Significance ◽  
Type Ii ◽  
Post Translational Modification ◽  
Post Translational Modifications ◽  
Chromatin Regulators ◽  
Cancer Types ◽  
Splicing Isoforms ◽  
Enrichment Techniques ◽  
Affect Cell Growth

The five human ING genes encode at least 15 splicing isoforms, most of which affect cell growth, differentiation and apoptosis through their ability to alter gene expression by epigenetic mechanisms. Since their discovery in 1996, ING proteins have been classified as type II tumour suppressors on the basis of reports describing their down-regulation and mislocalization in a variety of cancer types. In addition to their regulation by transcriptional mechanisms, understanding the range of PTMs (post-translational modifications) of INGs is important in understanding how ING functions are fine-tuned in the physiological setting and how they add to the repertoire of activities affected by the INGs. In the present paper we review the different PTMs that have been reported to occur on INGs. We discuss the PTMs that modulate ING function under normal conditions and in response to a variety of stresses. We also describe the ING PTMs that have been identified by several unbiased MS-based PTM enrichment techniques and subsequent proteomic analysis. Among the ING PTMs identified to date, a subset has been characterized for their biological significance and have been shown to affect processes including subcellular localization, interaction with enzymatic complexes and ING protein half-life. The present review aims to highlight the emerging role of PTMs in regulating ING function and to suggest additional pathways and functions where PTMs may effect ING function.

scholarly journals LSD1, a double-edged sword, confers dynamic chromatin regulation but commonly promotes aberrant cell growth

F1000Research ◽  
2017 ◽  
Vol 6 ◽  
pp. 2016 ◽  
Author(s):  
Meghan M Kozub ◽  
Ryan M Carr ◽  
Gwen L Lomberk ◽  
Martin E Fernandez-Zapico
Keyword(s):  
Gene Expression ◽  
Chromatin Remodeling ◽  
Cellular Differentiation ◽  
Critical Role ◽  
Histone Demethylase ◽  
Epigenetic Changes ◽  
Lysine Specific Demethylase ◽  
Wide Range ◽  
Histone Modifying Enzymes

Histone-modifying enzymes play a critical role in chromatin remodeling and are essential for influencing several genome processes such as gene expression and DNA repair, replication, and recombination. The discovery of lysine-specific demethylase 1 (LSD1), the first identified histone demethylase, dramatically revolutionized research in the field of epigenetics. LSD1 plays a pivotal role in a wide range of biological operations, including development, cellular differentiation, embryonic pluripotency, and disease (for example, cancer). This mini-review focuses on the role of LSD1 in chromatin regulatory complexes, its involvement in epigenetic changes throughout development, and its importance in physiological and pathological processes.

scholarly journals Histone acetylation recruits the SWR1 complex to regulate active DNA demethylation in Arabidopsis

2019 ◽  
Vol 116 (33) ◽  
pp. 16641-16650 ◽  
Author(s):  
Wen-Feng Nie ◽  
Mingguang Lei ◽  
Mingxuan Zhang ◽  
Kai Tang ◽  
Huan Huang ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Conceptual Framework ◽  
Histone Acetylation ◽  
Chromatin Remodeling ◽  
Nuclear Protein ◽  
Dna Demethylation ◽  
Specific Target ◽  
Active Dna Demethylation ◽  
Chromatin Remodeling Complex ◽  
Genomic Regions

Active DNA demethylation is critical for controlling the DNA methylomes in plants and mammals. However, little is known about how DNA demethylases are recruited to target loci, and the involvement of chromatin marks in this process. Here, we identify 2 components of the SWR1 chromatin-remodeling complex, PIE1 and ARP6, as required for ROS1-mediated DNA demethylation, and discover 2 SWR1-associated bromodomain-containing proteins, AtMBD9 and nuclear protein X1 (NPX1). AtMBD9 and NPX1 recognize histone acetylation marks established by increased DNA methylation 1 (IDM1), a known regulator of DNA demethylation, redundantly facilitating H2A.Z deposition at IDM1 target loci. We show that at some genomic regions, H2A.Z and DNA methylation marks coexist, and H2A.Z physically interacts with ROS1 to regulate DNA demethylation and antisilencing. Our results unveil a mechanism through which DNA demethylases can be recruited to specific target loci exhibiting particular histone marks, providing a conceptual framework to understand how chromatin marks regulate DNA demethylation.

scholarly journals Vitamin C Transporters and Their Implications in Carcinogenesis

Nutrients ◽  
2020 ◽  
Vol 12 (12) ◽  
pp. 3869
Author(s):  
Kinga Linowiecka ◽  
Marek Foksinski ◽  
Anna A. Brożyna
Keyword(s):  
Vitamin C ◽  
Cancer Biology ◽  
Redox Homeostasis ◽  
Regulation Of Gene Expression ◽  
Dna Demethylation ◽  
Altered Expression ◽  
Tet Proteins ◽  
Active Dna Demethylation ◽  
Hypoxic State

Vitamin C is implicated in various bodily functions due to its unique properties in redox homeostasis. Moreover, vitamin C also plays a great role in restoring the activity of 2-oxoglutarate and Fe2+ dependent dioxygenases (2-OGDD), which are involved in active DNA demethylation (TET proteins), the demethylation of histones, and hypoxia processes. Therefore, vitamin C may be engaged in the regulation of gene expression or in a hypoxic state. Hence, vitamin C has acquired great interest for its plausible effects on cancer treatment. Since its conceptualization, the role of vitamin C in cancer therapy has been a controversial and disputed issue. Vitamin C is transferred to the cells with sodium dependent transporters (SVCTs) and glucose transporters (GLUT). However, it is unknown whether the impaired function of these transporters may lead to carcinogenesis and tumor progression. Notably, previous studies have identified SVCTs’ polymorphisms or their altered expression in some types of cancer. This review discusses the potential effects of vitamin C and the impaired SVCT function in cancers. The variations in vitamin C transporter genes may regulate the active transport of vitamin C, and therefore have an impact on cancer risk, but further studies are needed to thoroughly elucidate their involvement in cancer biology.

scholarly journals L-Theanine Activates the Browning of White Adipose Tissue through the AMPK/α-Ketoglutarate/Prdm16 Axis and Ameliorates Diet-induced Obesity in Mice

2021 ◽  
Author(s):  
Wan-Qiu Peng ◽  
Gang Xiao ◽  
Bai-Yu Li ◽  
Ying-Ying Guo ◽  
Liang Guo ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
White Adipose Tissue ◽  
Intraperitoneal Administration ◽  
Dna Demethylation ◽  
Active Dna Demethylation ◽  
Diet Induced Obesity ◽  
Elevated Expression ◽  
Obesity In Mice

L-Theanine is a nonprotein amino acid with much beneficial efficacy. We found that intraperitoneal treatment of the mice with L-Theanine(100mg/kg/day) enhanced adaptive thermogenesis and induced the browning of inguinal white adipose tissue (iWAT) with elevated expression of Prdm16, Ucp1 and other thermogenic genes. Meanwhile, administration of the mice with L-Theanine increased energy expenditure. In vitro studies indicated that L-Theanine induced the development of brown-like features in adipocytes. The shRNA-mediated depletion of Prdm16 blunted the role of L-Theanine in promoting the brown-like phenotypes in adipocytes and in the iWAT of mice. L-Theanine treatment enhanced AMPKα phosphorylation both in adipocytes and in iWAT. Knockdown of AMPKα ablolished L-Theanine-induced upregulation of Prdm16 and adipocytes browning. L-Theanine increased the α-ketoglutarate (α-KG) level in adipocytes, which may increase the transcription of Prdm16 by inducing active DNA demethylation on its promoter. AMPK activation was required for L-Theanine-induced increase of α-KG and DNA demethylation on Prdm16 promoter. Moreover, intraperitoneal administration with L-Theanine ameliorated obesity, improved glucose tolerance and insulin sensitivity, and reduced plasma triglyceride, total cholesterol and free fatty acid in the high fat diet-fed mice. Our results suggest a potential role of L-Theanine in combating diet-induced obesity in mice, which may involve L-Theanine-induced browning of white adipose tissue.

Role of O-Linked N-acetylglucosamine (O-GlcNAc) Protein Modification in Cellular (Patho)Physiology

2020 ◽  
Author(s):  
John C. Chatham ◽  
Jianhua Zhang ◽  
Adam Raymond Wende
Keyword(s):  
Chromatin Remodeling ◽  
Protein Modification ◽  
Protein Localization ◽  
Cellular Functions ◽  
Secretory Pathways ◽  
Cellular Physiology ◽  
Cytoplasmic Proteins ◽  
Wide Range ◽  
Glcnac Transferase

In the mid 1980s, the identification of serine and threonine residues on nuclear and cytoplasmic proteins modified by an O-linkage by a N-acetylglucosamine moiety (O-GlcNAc) overturned the widely held assumption that glycosylation only occurred in the endoplasmic reticulum, Golgi apparatus, and secretory pathways. In contrast to traditional glycosylation, the O-GlcNAc modification does not lead to complex branched glycan structures and is rapidly cycled on and off proteins by O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA), respectively. Since its discovery O-GlcNAcylation has been shown to contribute to numerous cellular functions including signaling, protein localization and stability, transcription, chromatin remodeling, mitochondrial function, and cell survival. Dysregulation in O-GlcNAc cycling has been implicated in the progression of a wide range of diseases such as diabetes, diabetic complications, cancer, cardiovascular, and neurodegenerative diseases. This review will outline our current understanding of the processes involved in regulating O-GlcNAc turnover, the role of O-GlcNAcylation in regulating cellular physiology, and how dysregulation in O-GlcNAc cycling contributes to pathophysiological processes.

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