Huntington's disease (HD) is characterized by neuronal dysfunction and degeneration that varies markedly by brain region and cell type. We previously showed that CAG repeat expansion in exon 1 of the gene correlates with increased expression of the mismatch repair genes and in striatal medium spiny neurons, and demonstrated that, in the striatum and cerebral cortex of individuals with HD, hundreds of genes are dysregulated in neuronal cell types carrying somatically expanded CAG repeat in . Here we employ comprehensive epigenetic profiling in specific neuronal and glial cell types from the human striatum, cerebral cortex, hippocampus and cerebellum of control and HD donor samples to identify cell type- and species-specific transcriptional control mechanisms in the mismatch repair genes , and that can explain the specificity of somatic CAG expansion in the first stage of HD. In the second, toxic phase of HD we identify two distinct epigenetic mechanisms that disrupt regulation of hundreds of genes in the majority of HD MSNs, including several that cause haploinsufficient neurological disorders. Our data support a mechanistic model of HD pathogenesis in which regulation of mismatch repair gene transcription determines the selectivity of somatic expansion, and DNA methylation stabilizes the toxic effect of mutant huntingtin on HD-modifying proteins MED15 and TCERG1, which regulate enhancer function and transcription elongation.