Manipulating Histone H3 Methylation During Development: A Caenorhabditis Elegans Approach Toward Modeling Kabuki Syndrome.

Abstract

Sophisticated and highly coordinated mechanisms regulate histone methylation during development. In a diseased state this can give rise to multi-organ system congenital disorders such as Kabuki syndrome. The Caenorhabditis elegans animal model provides unique control in recapitulating genetic conditions relevant to disease states, as its genes are widely homologous to humans’ and its cellular development is well characterized. With this in mind, an experimental approach was designed to selectively depletion the key epigenetic regulators SET-16 or UTX-1, homologous in function to human KMT2D and KDM6A, respectively, malfunctions in which underly Kabuki syndrome. The auxin inducible degron (AID) system was shown to reliably induce targeted proteasomal degradation of SET-16 and UTX-1 resulting in changes to gene expression regulated by these factors, identified through transcriptomic analysis. The extent of auxin-induced depletion depended on both the concentration of auxin applied and the amount of time the animals were exposed. Early depletion of either SET-16 or UTX-1 consistently reduced the number of oocytes present, as well as overall fecundity. Genomic analysis indicates common changes in the expression patterns of at least 390 genes between both depletion scenarios, providing a list of potential genetic candidates for targeted treatment of Kabuki syndrome.