A001 Cell type specific somatic CAG expansion and epigenetic regulation in Huntington’s disease

<h3></h3> To understand molecular mechanisms accompanying progression in Huntington’s Disease (HD), our laboratory has employed FANS-seq, which allows deep profiling of transcription, chromatin accessibility, somatic CAG expansion, DNA methylation and hydroxymethylation, and histone modifications in specific cell types in human postmortem brain samples. This presentation will include data from analysis of the striatum, cerebral cortex, thalamus, hippocampus, and amygdala. Our data demonstrate that extensive somatic expansion occurs in specific cell types in each of these structures. To understand mechanisms altering gene expression during HD progression, and to identify regulatory elements that play important roles in somatic expansion, we will discuss mechanisms regulating enhancer function in specific classes of CNS neurons and glia that are species and cell type specific. We will present also epigenetic findings that correlate with altered transcription in cell types undergoing somatic CAG expansion, and discuss these data in light of mechanisms previously implicated in transcriptional dysregulation in HD. These discoveries emphasize the crucial role of cell-type specificity in unraveling both the molecular mechanisms underlying somatic CAG expansion and pathogenesis in HD.