Epigenetic and transcriptional modulation of WDR5, a chromatin remodeling protein, in Huntington's disease human induced pluripotent stem cell (hiPSC) model

- Global DNAm levels are higher in striatal differentiating HD-hiPSCs.
- Promoter hypermethylation in HD-hiPSCs is associated to HD-relevant pathways.
- Some JMJD3-related genes show aberrant promoter methylation and expression.
- WDR5 gene and protein expression is specifically down-modulated in HD-hiPSC lines.
- WDR5 down-modulation may indicate epigenomic deregulation in HD-hiPSCs.

DNA methylation (DNAm) changes are of increasing relevance to neurodegenerative disorders, including Huntington's disease (HD). We performed genome-wide screening of possible DNAm changes occurring during striatal differentiation in human induced pluripotent stem cells derived from a HD patient (HD-hiPSCs) as cellular model. We identified 240 differentially methylated regions (DMRs) at promoters in fully differentiated HD-hiPSCs. Subsequently, we focused on the methylation differences in a subcluster of genes related to Jumonji Domain Containing 3 (JMJD3), a demethylase that epigenetically regulates neuronal differentiation and activates neuronal progenitor associated genes, which are indispensable for neuronal fate acquisition. Noticeably among these genes, WD repeat-containing protein 5 (WDR5) promoter was found hypermethylated in HD-hiPSCs, resulting in a significant down-modulation in its expression and of the encoded protein. A similar WDR5 expression decrease was seen in a small series of HD-hiPSC lines characterized by different CAG length. The decrease in WDR5 expression was particularly evident in HD-hiPSCs compared to hESCs and control-hiPSCs from healthy subjects. WDR5 is a core component of the MLL/SET1 chromatin remodeling complexes essential for H3K4me3, previously reported to play an important role in stem cells self-renewal and differentiation. These results suggest the existence of epigenetic mechanisms in HD and the identification of genes, which are able to modulate HD phenotype, is important both for biomarker discovery and therapeutic interventions.