Histone Methylation Regulation in Neurodegenerative Disorders.

Balapal S Basavarajappa,Shivakumar Subbanna

doi:10.3390/ijms22094654

Abstract

Advances achieved with molecular biology and genomics technologies have permitted investigators to discover epigenetic mechanisms, such as DNA methylation and histone posttranslational modifications, which are critical for gene expression in almost all tissues and in brain health and disease. These advances have influenced much interest in understanding the dysregulation of epigenetic mechanisms in neurodegenerative disorders. Although these disorders diverge in their fundamental causes and pathophysiology, several involve the dysregulation of histone methylation-mediated gene expression. Interestingly, epigenetic remodeling via histone methylation in specific brain regions has been suggested to play a critical function in the neurobiology of psychiatric disorders, including that related to neurodegenerative diseases. Prominently, epigenetic dysregulation currently brings considerable interest as an essential player in neurodegenerative disorders, such as Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), Amyotrophic lateral sclerosis (ALS) and drugs of abuse, including alcohol abuse disorder, where it may facilitate connections between genetic and environmental risk factors or directly influence disease-specific pathological factors. We have discussed the current state of histone methylation, therapeutic strategies, and future perspectives for these disorders. While not somatically heritable, the enzymes responsible for histone methylation regulation, such as histone methyltransferases and demethylases in neurons, are dynamic and reversible. They have become promising potential therapeutic targets to treat or prevent several neurodegenerative disorders. These findings, along with clinical data, may provide links between molecular-level changes and behavioral differences and provide novel avenues through which the epigenome may be targeted early on in people at risk for neurodegenerative disorders.

Highlights

Neurodegenerative (ND) disorders are among the leading bases of disability and death worldwide [1,2,3]
Histone H3K79 di- and tri-methylation are catalyzed by DOT1L enzymes (KMT4) and are associated with gene expression activation [42]
The findings suggest the loss of neuronal polycomb repressive complex 2 (PRC2)-H3K27me3 sites and the upregulation of some PRC2 target genes associated mainly with Hox gene clusters and developmentally related proteins in the Huntington’s disease (HD)-affected human brain [125,126,127,128]

Summary

Introduction

Neurodegenerative (ND) disorders are among the leading bases of disability and death worldwide [1,2,3]. Despite decades of basic and clinical research, most strategies designed to reverse degenerative brain diseases are analgesic. This is not surprising as neurodegeneration progresses quietly for decades before the appearance of symptoms. Most important advances in sequencing technologies have allowed the mapping of transcriptomic patterns in human postmortem brain tissues in various ND disorders, including in vitro and in vivo cell and animal models. These investigations facilitated the discovery of classical neurodegeneration pathways and uncovered novel targets, including synaptic degeneration in the majority of ND, that share several puzzling characteristics. The current review discusses the critical advancements in epigenetic changes, histone methylation regulation in ND disorders

Epigenetic Changes

PTM of DNA-Associated Histone Proteins

Findings

Histone Demethylation