Modeling the effects of Huntington disease on age-related genes reveals CXXC4 as an epigenetic target to restore health and excitability of Drd1-expressing striatal neurons

Abstract

Gene profile studies suggest that neurons may face premature aging in neurodegenerative diseases such as Huntington disease (HD). Cells remodel gene expression to resist molecular damage in aging, but how neurons may engage age-related genes to resist HD remains unknown. Here, we found that transcriptional-aging inversion (TAGI) in the Drd1-expressing striatal neurons (Drd1 SNs) of HD knock-in (Hdh) mice shows discrete patterns in the backdrop of a TAG-like (TAGL) signature, and that TAGI persistence as Hdh mice become strongly symptomatic may better explain disease progression compared to TAGL dynamics. We also found that genes affected by 3prime UTR accumulation in aged mouse Drd1 SNs of aged mice are more likely downregulated in aging and deregulated in Hdh mice. Mapping 3prime UTR data in aging on gene dysregulation networks in the Drd1-SNs of weakly symptomatic Hdh mice highlighted a CAG repeat-dependent network of upregulated genes with compensatory potential as suggested by enrichment in development and maintenance factors such as CTCF. This class noticeably contains Atad-5, a PCNA unloader in the DNA repair complex and a modifier of CAG expansion in the plasma of HD patients. This class also contains CXXC4 (IDAX), an epigenetic regulator and repressor of TET2 activity, for which upregulation is lost in strongly symptomatic Hdh mice. CXXC4 reduces the levels of p16INK4a, a cellular senescence marker, in human iPS cell-derived SNs and restores glutamate excitability in human HD iPS cell-derived SNs. Collectively, these data suggest that the resilience capacity of Drd1 SNs against HD involves discrete patterns of age-related genes, where early intervention based on expressing broad-spectrum genes such as CXXC4 may provide novel therapeutic strategies to restore cortico-striatal homeostasis and function.