Epigenetic features in hESC-derived neuronal cells carrying the Huntington’s Disease gene

Huntington’s Disease is a neurodegenerative disorder caused by an expansion of CAG repeats (>35) in the huntingtin (HTT) gene. This mutation results in the progressive degeneration of specific brain neurons, particularly the medium spiny neurons (MSNs) in the striatum, leading to atrophy.

While HD symptoms typically manifest in adulthood, there is growing evidence suggesting a neurodevelopmental component in the pathology. HTT interacts with various developmental regulatory factors and plays a vital role in multiple aspects of neurodevelopment, including neuronal tube formation, maturation, and survival. One of these factors is PRC2, a chromatin-modifying factor that collaborates with Trithorax Group Proteins to maintain the pluripotent state of embryonic stem cells (ESCs).

Based on these findings, our research focuses on characterizing the epigenetic features during in vitro differentiation of an isogenic panel of human embryonic stem cell lines carrying a gradual increase in CAG length in the HTT gene. Initially, we conducted immunocytochemistry at different time points during in vitro maturation, which revealed abnormal differentiation and persistent expression of the pluripotent marker Oct4 at later stages of differentiation in the presence of mutant HTT. These observations suggest the presence of chromatin abnormalities in the HD lines at early stages. We then performed a whole-genome analysis using ChIP-seq to investigate different epigenetic histone modifications. The aim is to identify whether there is an epigenetic signature in the HD lines and how it evolves during differentiation. Both ChIP-seq and RNA-seq analyses are currently underway, and the results will be presented.