scholarly journals DNA Methylation in Huntington’s Disease

2021 ◽  
Vol 22 (23) ◽  
pp. 12736
Author(s):  
Nóra Zsindely ◽  
Fruzsina Siági ◽  
László Bodai
Keyword(s):  
Dna Methylation ◽  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Mammalian Cells ◽  
Metabolic Diseases ◽  
Single Gene ◽  
Epigenetic Inheritance ◽  
Current Evidence ◽  
Inherited Disease ◽  
Cpg Dinucleotides

Methylation of cytosine in CpG dinucleotides is the major DNA modification in mammalian cells that is a key component of stable epigenetic marks. This modification, which on the one hand is reversible, while on the other hand, can be maintained through successive rounds of replication plays roles in gene regulation, genome maintenance, transgenerational epigenetic inheritance, and imprinting. Disturbed DNA methylation contributes to a wide array of human diseases from single-gene disorders to sporadic metabolic diseases or cancer. DNA methylation was also shown to affect several neurodegenerative disorders, including Huntington’s disease (HD), a fatal, monogenic inherited disease. HD is caused by a polyglutamine repeat expansion in the Huntingtin protein that brings about a multifaceted pathogenesis affecting several cellular processes. Research of the last decade found complex, genome-wide DNA methylation changes in HD pathogenesis that modulate transcriptional activity and genome stability. This article reviews current evidence that sheds light on the role of DNA methylation in HD.

scholarly journals DNA Methylation in Solid Tumors: Functions and Methods of Detection

2021 ◽  
Vol 22 (8) ◽  
pp. 4247
Author(s):  
Andrea Martisova ◽  
Jitka Holcakova ◽  
Nasim Izadi ◽  
Ravery Sebuyoya ◽  
Roman Hrstka ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Solid Tumors ◽  
Epigenetic Modification ◽  
Single Gene ◽  
Restriction Enzymes ◽  
Methylation Analysis ◽  
Cpg Dinucleotides ◽  
Sequencing Technologies ◽  
Genome Level ◽  
Dna Methylation Analysis

DNA methylation, i.e., addition of methyl group to 5′-carbon of cytosine residues in CpG dinucleotides, is an important epigenetic modification regulating gene expression, and thus implied in many cellular processes. Deregulation of DNA methylation is strongly associated with onset of various diseases, including cancer. Here, we review how DNA methylation affects carcinogenesis process and give examples of solid tumors where aberrant DNA methylation is often present. We explain principles of methods developed for DNA methylation analysis at both single gene and whole genome level, based on (i) sodium bisulfite conversion, (ii) methylation-sensitive restriction enzymes, and (iii) interactions of 5-methylcytosine (5mC) with methyl-binding proteins or antibodies against 5mC. In addition to standard methods, we describe recent advances in next generation sequencing technologies applied to DNA methylation analysis, as well as in development of biosensors that represent their cheaper and faster alternatives. Most importantly, we highlight not only advantages, but also disadvantages and challenges of each method.

scholarly journals HDAC inhibition imparts beneficial transgenerational effects in Huntington's disease mice via altered DNA and histone methylation

2014 ◽  
Vol 112 (1) ◽  
pp. E56-E64 ◽  
Author(s):  
Haiqun Jia ◽  
Charles D. Morris ◽  
Roy M. Williams ◽  
Jeanne F. Loring ◽  
Elizabeth A. Thomas
Keyword(s):  
Dna Methylation ◽  
Transgenic Mice ◽  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Hdac Inhibitors ◽  
Hdac Inhibition ◽  
Transgenerational Effects ◽  
Treated Male ◽  
Disease Phenotypes ◽  
Cpg Sites

Increasing evidence has demonstrated that epigenetic factors can profoundly influence gene expression and, in turn, influence resistance or susceptibility to disease. Epigenetic drugs, such as histone deacetylase (HDAC) inhibitors, are finding their way into clinical practice, although their exact mechanisms of action are unclear. To identify mechanisms associated with HDAC inhibition, we performed microarray analysis on brain and muscle samples treated with the HDAC1/3-targeting inhibitor, HDACi 4b. Pathways analyses of microarray datasets implicate DNA methylation as significantly associated with HDAC inhibition. Further assessment of DNA methylation changes elicited by HDACi 4b in human fibroblasts from normal controls and patients with Huntington’s disease (HD) using the Infinium HumanMethylation450 BeadChip revealed a limited, but overlapping, subset of methylated CpG sites that were altered by HDAC inhibition in both normal and HD cells. Among the altered loci of Y chromosome-linked genes, KDM5D, which encodes Lys (K)-specific demethylase 5D, showed increased methylation at several CpG sites in both normal and HD cells, as well as in DNA isolated from sperm from drug-treated male mice. Further, we demonstrate that first filial generation (F1) offspring from drug-treated male HD transgenic mice show significantly improved HD disease phenotypes compared with F1 offspring from vehicle-treated male HD transgenic mice, in association with increased Kdm5d expression, and decreased histone H3 Lys4 (K4) (H3K4) methylation in the CNS of male offspring. Additionally, we show that overexpression of Kdm5d in mutant HD striatal cells significantly improves metabolic deficits. These findings indicate that HDAC inhibitors can elicit transgenerational effects, via cross-talk between different epigenetic mechanisms, to have an impact on disease phenotypes in a beneficial manner.

scholarly journals DNA Methylation Profiles in Whole Blood of Huntington's Disease Patients

2018 ◽  
Vol 9 ◽  
Author(s):  
Maja Zadel ◽  
Aleš Maver ◽  
Anja Kovanda ◽  
Borut Peterlin
Keyword(s):  
Dna Methylation ◽  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Whole Blood

scholarly journals Huntington's disease accelerates epigenetic aging of human brain and disrupts DNA methylation levels

Aging ◽  
2016 ◽  
Vol 8 (7) ◽  
pp. 1485-1512 ◽  
Author(s):  
Steve Horvath ◽  
Peter Langfelder ◽  
Seung Kwak ◽  
Jeff Aaronson ◽  
Jim Rosinski ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Human Brain ◽  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Epigenetic Aging

Biocultures: An Emerging Paradigm

PMLA ◽  
2009 ◽  
Vol 124 (3) ◽  
pp. 947-949 ◽  
Author(s):  
Jay Clayton
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Single Gene ◽  
Extreme Case ◽  
Emotional Control ◽  
Genetic Abnormality ◽  
Medical Experience ◽  
The Poor ◽  
Ian Mcewan ◽  
Single Sequence

Literature and Science Policy: A New Project for the HumanitiesThe misfortune lies with a single gene, in an excessive repeat of a single sequence—CAG. Here's biological determinism in its purest form. More than forty repeats of that one little codon, and you're doomed.—Ian McEwan, Saturday (94)Huntington's disease. Perowne, the neurosurgeon in Ian McEwan's novel Saturday (2005), readily diagnoses the genetic abnormality that afflicts a petty criminal who is assaulting him. It is like a tic with Perowne. He cannot stop himself from analyzing the biological causes of the poor emotional control, the violent temper, of the man who is mugging him. Perowne regards himself as a “professional reductionist,” a man of science who “can't help thinking it's down to invisible folds and kinks of character, written in code, at the level of molecules” (281). A lifetime of medical experience has led him to conclude that much of our behavior is dictated by biology. But Huntington's disease represents an extreme case. For someone with this condition, the “future is fixed and easily foretold” (94).

scholarly journals New Perspectives on Emotional Processing in People with Symptomatic Huntington’s Disease: Impaired Emotion Regulation and Recognition of Emotional Body Language†

2018 ◽  
Vol 34 (5) ◽  
pp. 610-624 ◽  
Author(s):  
Nicolò Zarotti ◽  
Ian Fletcher ◽  
Jane Simpson
Keyword(s):  
Emotion Regulation ◽  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Emotional Processing ◽  
Neurodegenerative Disorder ◽  
Body Language ◽  
Disease Stage ◽  
Current Evidence ◽  
Future Research ◽  
Clinical Conditions

Abstract Objective Emotion regulation and emotional body language (EBL) recognition represent two fundamental components of emotional processing that have recently seen a considerable surge in research interest, in part due to the role they play in optimizing mental health. This appears to be particularly true for clinical conditions that can profoundly affect emotional functioning. Among these is Huntington’s disease (HD), a neurodegenerative disorder that is associated with several psychological difficulties and cognitive impairments, including well-established deficits in facial emotion recognition. However, although the theoretical case for impairments is strong, the current evidence in HD on other components such as emotion regulation and EBL recognition is sparse. Method In this study, it was hypothesized that emotion regulation and recognition of EBL are impaired in people with symptomatic HD, and that these impairments significantly and positively correlate with each other. A between-subjects design was adopted to compare 13 people with symptomatic HD with 12 non-affected controls matched for age and education. Results The results showed that emotion regulation and EBL recognition were significantly impaired in individuals with HD. Moreover, a significant positive correlation was observed between facial and EBL recognition impairments, whereas EBL performance was negatively related to the disease stage. However, emotion regulation and recognition performances were not significantly correlated. Conclusions This investigation represents the first evidence of a deficit of emotion regulation and EBL recognition in individuals with HD. The clinical implications of these findings are explored, and indications for future research are proposed.

B13 Can Dna Methylation Be A Factor In The Pathogenesis Of Huntington's Disease?

2014 ◽  
Vol 85 (Suppl 1) ◽  
pp. A13-A13
Author(s):  
A. Stanis awska-Sachadyn ◽  
M. Krygier ◽  
S. Bara ska ◽  
P. J drak ◽  
W. So tan ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Huntington's Disease ◽  
Huntington’S Disease

scholarly journals TBK1 regulates autophagic clearance of soluble mutant huntingtin and inhibits aggregation/toxicity in different models of Huntington’s disease

2019 ◽  
Author(s):  
Ramanath Narayana Hegde ◽  
Anass Chiki ◽  
Lara Petricca ◽  
Paola Martufi ◽  
Nicolas Arbez ◽  
...  
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Mammalian Cells ◽  
Neuronal Cultures ◽  
Autophagic Flux ◽  
Primary Neurons ◽  
Wild Type ◽  
Neuroprotective Effects ◽  
Dependent Inhibition

AbstractPhosphorylation of the N-terminal domain of the Huntingtin (HTT) protein (at T3, S13, and S16) has emerged as a key regulator of HTT stability, clearance, localization, aggregation and toxicity. Herein, we report the discovery and validation of a kinase, TANK-binding kinase 1 (TBK1), that specifically and efficiently phosphorylates both wild-type and mutant full-length or N-terminal fragments of HTT in vitro (S13/S16) and in cell/ neuronal cultures (S13). We show that overexpression of TBK1 in mammalian cells, primary neurons and a Caenorhabditis elegans model of Huntington’s Disease (HD) increases mutant HTTex1 phosphorylation, lowers its levels, increases its nuclear localization and significantly reduces its aggregation and cytotoxicity. Our mechanistic studies demonstrate that the TBK1-mediated neuroprotective effects are due to phosphorylation-dependent inhibition of mutant HTTex1 aggregation and an increase in autophagic flux. These findings suggest that upregulation and/or activation of TBK1 represents a viable strategy for the treatment of HD.Graphical abstract

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