Partial depletion of C. elegans SET-16/KMT2D and UTX-1/KDM6A

Many human genetic disorders are caused by heterozygous mutations that moderately reduce protein levels. We used the auxin-inducible degron (AID) system to achieve quantitatively reproducible partial protein depletion over a wide range of levels in C. elegans. We focused on SET-16/KMT2D and UTX-1/KDM6A, histone-modifying enzymes that are associated with the developmental disorder Kabuki Syndrome (KS). We inserted a tandem AID-GFP tag in the endogenous set-16 and utx-1 genes and found that 0, 0.01, 0.1, or 1.0 mM auxin resulted respectively in 100%, 74%, 24%, and 1% SET-16 levels in somatic cells. Next, we used transcriptional profiling to identify ~2000 genes whose expression correlated with SET-16 and UTX-1 levels. Our results demonstrate that even a modest decrease in protein levels elicits a widespread dose-dependent transcriptional response.