Alterations in epigenetic regulation contribute to neurodegeneration of ataxia-telangiectasia

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.