Histone hyperacetylation-linked upregulation of KRAB zinc finger proteins impedes glial differentiation in Huntington's disease

Abstract

Glial differentiation is impaired in Huntington disease (HD), contributing to both the synaptic dysfunction and hypomyelination of HD. Through combined epigenomic and transcriptomic profiling, we found that glial progenitor cells (hGPCs) generated from HD-derived human embryonic stem cells exhibit persistent histone hyperacetylation, enabling the ectopic expression of a broad set of KRAB zinc finger protein (KZFP) transcriptional repressors. Single-cell RNA-Seq analysis of HD hGPCs revealed that their aberrant KZFP expression was attended by the persistent expression of neural progenitor-stage genes relative to wild-type hGPCs. The HD hGPCs over-expressed the MYST family histone acetyltransferase KAT6B, which led to their hyperacetylation at H3K9 and associated DNA demethylation, and displayed abnormally open chromatin, particularly at promoters of chromosome 19 KZFP gene clusters. Among those KZFPs most differentially activated in HD hGPCs was the primate-specific ZNF98, whose overexpression in wild-type hGPCs recapitulated the HD-associated suppression of glial development. These data implicate abnormal histone hyperacetylation in HD glial progenitor cells, and its associated over-expression of recently evolved KZFP transcriptional repressors, as a critical mechanism by which both astrocytic and oligodendrocytic differentiation are impaired in HD.