Age-associated chromatin relaxation is enhanced in Huntington's disease mice.

Myungsun Park,Jisun Kim,Jinhoi Song,Sunwha Cho,Seokho Kim,Byungkuk Min,Kyuheum Jeon,Jeha Jeon,Jung Sun Park,Hyemyung Seo,Yong-Kook Kang,Sangkyun Jeong

doi:10.18632/aging.101193

Abstract

Expansion of polyglutamine stretch in the huntingtin (HTT) protein is a major cause of Huntington's disease (HD). The polyglutamine part in HTT interacts with various proteins implicated in epigenetic regulation of genes, suggesting that mutant HTT may disturb the integrity of the epigenetic system. Here, we used a PCRseq-based method to examine expression profile of 395 exonic segments from 260 “epi-driver” genes in splenic T lymphocytes from aged HD mice. We identified 67 exonic segments differentially expressed between young and aged HD mice, most of them upregulated in the aged. Polycomb-repressive complex (PRC)-regulated genes (PRGs) were markedly upregulated in aged HD mice, consistent with downregulation of PRC genes. Epi-driver gene categories of lysine-methylation, lysine-demethylation, arginine-methylation, and PRG showed differential age-associated changes between HD and control. Analyzing the pattern of change in epi-driver gene expressions hinted at an enhanced shift in HD chromatin to a more accessible state with age, which was experimentally demonstrated by DNase-I-hypersensitivity sequencing showing increased chromatin accessibility in HD cells compared to control. We suggest the global change can potentially relieve chromatin-induced repression of many genes, and the unintended expressions of some detrimental proteins could alter T cell function to a greater degree in aged HD mice.

Highlights

Huntington’s disease (HD) is caused by a mutation that leads to an expansion of a polyglutamine stretch in the huntingtin (HTT) protein
We included senescenceassociated genes and developmental genes regulated by Polycomb group (PcG) proteins; they were selected www.aging-us.com based on our own research interests and gleaned from a variety of recent research papers
One important theme about key signature of aging chromatin or epigenetic drift is the loss of repressive marks and gain of activating marks that have profound effects on gene expression [36]

Summary

Introduction

Huntington’s disease (HD) is caused by a mutation that leads to an expansion of a polyglutamine stretch in the huntingtin (HTT) protein. Disease pathology has been traditionally confined to the central nervous system; mutated huntingtin (mHTT) is ubiquitously expressed throughout the body in humans and other mammals [1,2,3,4]. Immune-system dysfunction is a noticeable symptom of HD pathogenesis in the periphery, where characteristic increase in the levels of circulating proinflammatory cytokines [11] and chemokines [12] are observed in the blood many years prior to disease onset. The level of mHTT in T lymphocytes was correlated with disease-burden scores and caudate atrophy [16]. These collective findings suggest that mHTT expression causatively affects immune-system integrity and T lymphocyte function

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Conclusion