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

  • Cell Rep. 2026 Jun 19;45(7):117584. doi: 10.1016/j.celrep.2026.117584.
Leijie Xie  1 ,  Xiaodong Liu  1 ,  Can Zhang  1 ,  Xinyi Niu  1 ,  Laiqiang Chen  2 ,  Gongke Zhou  1 ,  Mingyang Zhu  1 ,  Caijuan Li  1 ,  Huichun Tong  2 ,  Sen Yan  3 ,  Xiao-Jiang Li  4 ,  Shihua Li  5 ,  Li Lin  6
Affiliations
  • 1. State Key Laboratory of Bioactive Molecules and Druggability Assessment, Guangdong Basic Research Center of Excellence for Natural Bioactive Molecules and Discovery of Innovative Drugs, Guangdong-Hong Kong-Macau Institute of CNS Regeneration, Jinan University, Guangzhou, China; Guangdong Provincial Key Laboratory of Non-human Primate Research, Jinan University, Guangzhou, China.
  • 2. State Key Laboratory of Bioactive Molecules and Druggability Assessment, Guangdong Basic Research Center of Excellence for Natural Bioactive Molecules and Discovery of Innovative Drugs, Guangdong-Hong Kong-Macau Institute of CNS Regeneration, Jinan University, Guangzhou, China; Department of Neurosurgery, The First Affiliated Hospital of Jinan University, Guangzhou, China.
  • 3. State Key Laboratory of Bioactive Molecules and Druggability Assessment, Guangdong Basic Research Center of Excellence for Natural Bioactive Molecules and Discovery of Innovative Drugs, Guangdong-Hong Kong-Macau Institute of CNS Regeneration, Jinan University, Guangzhou, China; Guangdong Provincial Key Laboratory of Non-human Primate Research, Jinan University, Guangzhou, China. Electronic address: [email protected].
  • 4. State Key Laboratory of Bioactive Molecules and Druggability Assessment, Guangdong Basic Research Center of Excellence for Natural Bioactive Molecules and Discovery of Innovative Drugs, Guangdong-Hong Kong-Macau Institute of CNS Regeneration, Jinan University, Guangzhou, China; Guangdong Provincial Key Laboratory of Non-human Primate Research, Jinan University, Guangzhou, China; Lingang Laboratory, Building 37, No. 2380 Hechuan Road, Minhang District, Shanghai, China. Electronic address: [email protected].
  • 5. State Key Laboratory of Bioactive Molecules and Druggability Assessment, Guangdong Basic Research Center of Excellence for Natural Bioactive Molecules and Discovery of Innovative Drugs, Guangdong-Hong Kong-Macau Institute of CNS Regeneration, Jinan University, Guangzhou, China; Guangdong Provincial Key Laboratory of Non-human Primate Research, Jinan University, Guangzhou, China. Electronic address: [email protected].
  • 6. State Key Laboratory of Bioactive Molecules and Druggability Assessment, Guangdong Basic Research Center of Excellence for Natural Bioactive Molecules and Discovery of Innovative Drugs, Guangdong-Hong Kong-Macau Institute of CNS Regeneration, Jinan University, Guangzhou, China; Guangdong Provincial Key Laboratory of Non-human Primate Research, Jinan University, Guangzhou, China. Electronic address: [email protected].
PMID: 42322611 DOI: 10.1016/j.celrep.2026.117584
Abstract

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.

Keywords
5-hydroxymethylcytosine; 5-methylcytosine; CP: molecular biology; CP: neuroscience; DNA methylation; TBP; TET1; huntingtin; pig.
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