Abstract
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.
Highlights
Huntington’s disease (HD) is a monogenic dominant neurodegenerative disorder that mainly affects the striatum but other areas of the brain are impacted
HD is characterized by multifaceted pathogenesis that includes alterations of the chromatin landscape. mutant Htt (mHtt) provokes changes in the level or activity of transcriptional factors, chromatin-modifying factors, and enzymes involved in CpG methylation (DNMTs) and demethylation (TETs) directly or indirectly
The concerted action of these factors leads to complex changes in DNA methylation in HD, that include simultaneous hyper- or hypomethylation of specific CpG sites residing in different parts of the genome including both
Summary
Huntington’s disease (HD) is a monogenic dominant neurodegenerative disorder that mainly affects the striatum but other areas of the brain are impacted. The disease is caused by a dominant gain of function in the huntingtin (HTT, IT15) gene located in the cytogenetic position 4p16.3 [2]. In the first exon of HTT, there is a polymorphic, unstable CAG trinucleotide repeat sequence that is translated to a polyglutamine (polyQ) repeat close to the N-terminus of Htt. The disease-causing mutation is an increase in the repeat number of the CAG repeat that results in an elongated polyQ domain in the mutant Htt (mHtt) protein. Mutant Huntingtin modulates the level or activity of specific transcriptional factors, such as Elk-1, SMAD3, Sp1, or Twist1 [4,6,7,8], and disturbs transcriptional control by affecting processes regulating the structure and accessibility of chromatin, including histone methylation, histone acetylation and DNA methylation [9,10,11]. We overview the body of knowledge accumulated about altered DNA methylation and its implications in the pathology of Huntington’s disease
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