Contribution of neuroepigenetics to HD – developmental and aging-related signatures

Huntington's disease (HD) is a neurodegenerative disorder triggered by an unstable expansion of CAG repeats in the coding sequence of the <i>HTT</i> gene. Among the neuronal populations affected, striatal spiny projection neurons (SPNs) show particular susceptibility to the pathogenic mutation. The basis of this selective vulnerability, however, is still not fully understood. In this review, we highlight recent epigenomic research on HD, framing it within current concepts in epigenetics. We propose that epigenetic regulation contributes to neuronal vulnerability in HD. Functional genomics studies provide growing evidence in support of this view. Findings from both HD animal models and patient-derived tissues have shown somatic CAG expansion-dependent epigenetic and transcription erosion in vulnerable neurons, which leads to accelerated loss of the identity of vulnerable neurons, promoting their premature aging. Moreover, HD stem cell models show that epigenetic and transcriptional alterations also occur during neural differentiation, impacting neuronal specification and maturation trajectories. This suggests that abnormal epigenetic priming during neurodevelopment might further predispose vulnerable neurons to later epigenetic and transcriptional erosion, thereby amplifying their susceptibility in the disease.