Alterations in epigenetic regulation contribute to neurodegeneration of ataxia-telangiectasia

TY - CHAP

T1 - Alterations in epigenetic regulation contribute to neurodegeneration of ataxia-telangiectasia

AU - Li, Jiali

AU - Herrup, Karl

N1 - Publisher Copyright: © 2019 Elsevier Inc. All rights reserved.

PY - 2019/1/1

Y1 - 2019/1/1

N2 - The concept of involvement of epigenetic dysregulation in the neurodegeneration of Ataxia-telangiectasia (A-T) patients has strongly gained ground in recent years. Abnormal changes in multiple epigenetic regulations essentially necessitate that A-T mutated (ATM) deficiency leads to nuclear accumulation of histone deacetylase 4, elevated H3K27me3, and deregulated active DNA demethylation. Alternately, such alterations in distinct epigenetic systems may also be reacquired through cell cycle reentry and abnormal DNA-damage response (DDR) in ATM deficiency. In particular, loss of 5-hydroxymethylcytosine (5-hmC) plays a key role in Purkinje cell vulnerability in A-T brain. Meanwhile, ten-eleven translocation dioxygenase (TET1)- and TET3-mediated DNA demethylation directly regulate ATM- and ataxia telangiectasia and Rad3-related protein (ATR)-dependent DDR. In this chapter, the recent advances in elucidating epigenetic bases that regulate the A-T neurodegeneration and ATM/ATR-dependent DNA-damage signaling will be presented.

AB - The concept of involvement of epigenetic dysregulation in the neurodegeneration of Ataxia-telangiectasia (A-T) patients has strongly gained ground in recent years. Abnormal changes in multiple epigenetic regulations essentially necessitate that A-T mutated (ATM) deficiency leads to nuclear accumulation of histone deacetylase 4, elevated H3K27me3, and deregulated active DNA demethylation. Alternately, such alterations in distinct epigenetic systems may also be reacquired through cell cycle reentry and abnormal DNA-damage response (DDR) in ATM deficiency. In particular, loss of 5-hydroxymethylcytosine (5-hmC) plays a key role in Purkinje cell vulnerability in A-T brain. Meanwhile, ten-eleven translocation dioxygenase (TET1)- and TET3-mediated DNA demethylation directly regulate ATM- and ataxia telangiectasia and Rad3-related protein (ATR)-dependent DDR. In this chapter, the recent advances in elucidating epigenetic bases that regulate the A-T neurodegeneration and ATM/ATR-dependent DNA-damage signaling will be presented.

KW - Ataxia-telangiectasia

KW - DNA demethylation

KW - EZH2

KW - Epigenetics

KW - H3K27me3

KW - HDAC4

UR - https://www.scopus.com/pages/publications/85124853972

U2 - 10.1016/B978-0-12-813796-3.00006-7

DO - 10.1016/B978-0-12-813796-3.00006-7

M3 - Chapter

SP - 119

EP - 133

BT - Chromatin Signaling and Neurological Disorders

PB - Elsevier

ER -