Mutant huntingtin disrupts TET1 transcription and alters DNA methylation in a Huntington’s disease knock-in pig model

Abnormal DNA methylation occurs in Huntington's disease (HD, but the underlying mechanisms remain unclear. Using a knock-in pig model, we identify significant alterations in 5mC and 5hmC levels linked to neural genes. TET1, which converts 5mC to 5hmC, decreases prior to symptom onset in pigs—a change not observed in HD mice. TBP binding sites are abundant in the porcine and human TET1 promoter, but scarce in mice. Mutant huntingtin (mHTT) binds more strongly to TBP in HD pig brains, blocking TBP's access to the TET1 promoter, thereby reducing TET1 transcription and altering 5mC/5hmC patterns. Our findings reveal TET1 as a target of abnormal DNA methylation that contributes to selective neuronal vulnerability in HD pigs, highlighting the value of large mammalian models for studying disease pathogenesis.