RT Journal Article SR Electronic T1 Epigenomic analysis of Parkinson’s disease neurons identifies Tet2 loss as neuroprotective JF bioRxiv FD Cold Spring Harbor Laboratory SP 779785 DO 10.1101/779785 A1 Marshall Lee A1 Killinger Bryan A1 Li Peipei A1 Ensink Elizabeth A1 Li Katie A1 Cui Wei A1 Lubben Noah A1 Weiland Matthew A1 Gordevicius Juozas A1 Coetzee Gerhard A. A1 Jovinge Stefan A1 Labrie Viviane YR 2019 UL http://biorxiv.org/content/early/2019/09/24/779785.abstract AB PD pathogenesis may involve the epigenetic control of enhancers that modify neuronal functions. Here, we comprehensively profile DNA methylation at enhancers, genome-wide, in neurons of 57 PD patients and 48 control individuals. We found a widespread increase in cytosine modifications at enhancers in PD neurons, which is partly explained by elevated hydroxymethylation levels. Epigenetic dysregulation of enhancers in PD converge on transcriptional abnormalities affecting neuronal signaling and immune activation pathways. In particular, PD patients exhibit an epigenetic and transcriptional upregulation of TET2, a master-regulator of cytosine modification status. TET2 inactivation in a neuronal cell line results in cytosine modification changes that are reciprocal to those observed in PD neurons. Furthermore, Tet2 inactivation in mice fully prevents dopaminergic neuronal loss in the substantia nigra induced by prior inflammation. Tet2 loss in mice also attenuates transcriptional immune responses to an inflammatory trigger. Thus, widespread epigenetic dysregulation of enhancers in PD neurons may, in part, be mediated by increased TET2 expression. Decreased Tet2 activity is neuroprotective, in vivo, and may be a novel therapeutic target for PD.