LAUSR

Kabuki syndrome (KS) is frequently caused by loss-of-function mutations in one allele of the H3K4 methyltransferase KMT2D and is associated with problems in neurological, immunological, and skeletal system development. We generated heterozygous KMT2D knock-out and Kabuki-patient derived cell models to investigate the role of KMT2D reduced dosage in stem cells. We discovered chromosomal locus-specific alterations in gene expression, specifically a 110Kb region containing SYT3, CLEC11A, C19ORF81, and SHANK1, suggesting locus-specific targeting of KMT2D. Using whole genome histone methylation mapping, we confirmed locus-specific changes in H3K4 methylation patterning co-incident with regional decreases in gene expression in Kabuki cell models. Significantly reduced H3K4 peaks aligned with regions of stem cell maps of H3K27 and H3K4 methylation, suggesting KMT2D haploinsufficiency impacts bivalent enhancers in stem cells. Preparing the genome for subsequent differentiation cues may be of significant importance for Kabuki-related genes. This work provides new insight into the mechanism of action of an important gene in bone and brain development and may increase our understanding of a specific function of a human disease-relevant H3K4 methyltransferase family member.