DNA methylation study of Huntington's disease and motor progression in patients and in animal models.

ABSTRACT: Although Huntington's disease (HD) is a well studied Mendelian genetic disorder, less is known about its associated epigenetic changes. Here, we characterize DNA methylation levels in six different tissues from 3 species: a mouse huntingtin (Htt) gene knock-in model, a transgenic HTT sheep model, and humans. Our epigenome-wide association study (EWAS) of human blood reveals that HD mutation status is significantly (p?-7) associated with 33 CpG sites, including the HTT gene (p?=?6.5?×?10^-26). These Htt/HTT associations were replicated in the Q175 Htt knock-in mouse model (p?=?6.0?×?10^-8) and in the transgenic sheep model (p?=?2.4?×?10^-88). We define a measure of HD motor score progression among manifest HD cases based on multiple clinical assessments. EWAS of motor progression in manifest HD cases exhibits significant (p?-7) associations with methylation levels at three loci: near PEX14 (p?=?9.3?×?10^-9), GRIK4 (p?=?3.0?×?10^-8), and COX4I2 (p?=?6.5?×?10^-8). We conclude that HD is accompanied by profound changes of DNA methylation levels in three mammalian species.

SUBMITTER: Lu AT 

PROVIDER: S-EPMC7484780 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature