Abstract
BackgroundHuntington’s Disease (HD) is a fatal neurodegenerative disorder caused by a CAG repeat expansion, resulting in a mutant huntingtin protein. While it is now clear that astrocytes are affected by HD and significantly contribute to neuronal dysfunction and pathogenesis, the alterations in the transcriptional and epigenetic profiles in HD astrocytes have yet to be characterized. Here, we examine global transcription and chromatin accessibility dynamics during in vitro astrocyte differentiation in a transgenic non-human primate model of HD.ResultsWe found global changes in accessibility and transcription across different stages of HD pluripotent stem cell differentiation, with distinct trends first observed in neural progenitor cells (NPCs), once cells have committed to a neural lineage. Transcription of p53 signaling and cell cycle pathway genes was highly impacted during differentiation, with depletion in HD NPCs and upregulation in HD astrocytes. E2F target genes also displayed this inverse expression pattern, and strong associations between E2F target gene expression and accessibility at nearby putative enhancers were observed.ConclusionsThe results suggest that chromatin accessibility and transcription are altered throughout in vitro HD astrocyte differentiation and provide evidence that E2F dysregulation contributes to aberrant cell-cycle re-entry and apoptosis throughout the progression from NPCs to astrocytes.
Highlights
Huntington’s Disease (HD) is a fatal neurodegenerative disorder caused by a CAG repeat expansion, resulting in a mutant huntingtin protein
It has been demonstrated that mutant huntingtin protein (mHTT) aberrantly interacts with and sequesters critical proteins, such as transcription factors (TFs) and enzymes involved in epigenetic processes, causing widespread changes in transcription and disruption of important cellular processes in the brain [1, 8, 29,30,31,32,33,34,35,36,37]
In vitro astrocyte differentiation of HD and WT Rhesus macaque cells Stable neural progenitor cells (NPCs) lines were previously established from HD and WT Rhesus macaque pluripotent stem cells (PSCs) [89]
Summary
Huntington’s Disease (HD) is a fatal neurodegenerative disorder caused by a CAG repeat expansion, resulting in a mutant huntingtin protein. The disruption of many cellular processes, including neurodevelopment, cell cycle, apoptosis, mitochondrial function, inflammation, and synapse formation and activity by mHTT in neurons is well documented, but incompletely understood [16,17,18,19,20,21]. It has been demonstrated that mHTT aberrantly interacts with and sequesters critical proteins, such as transcription factors (TFs) and enzymes involved in epigenetic processes, causing widespread changes in transcription and disruption of important cellular processes in the brain [1, 8, 29,30,31,32,33,34,35,36,37]. The downstream transcriptome consequences of the mHTT interactions with TFs, such as p53, are not well understood
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