Chromatin modifying enzymes in neurodevelopmental disorders

Over the last decade, human genetic studies have found that genes encoding chromatin modifying and interacting proteins are frequent causes of neurodevelopmental disorders. In fact, >30% of high-confidence autism and intellectual disability risk genes encode chromatin-modifying factors.

Research in my group has focused on factors that interact with and regulate chromatin modified by a specific modification, methylation of lysine 4 on histone 3 (H3K4me). Loss of function mutations in genes encoding lysine methyltransferases (KMTs) responsible for H3K4 methylation, as well as ATP-dependent chromatin remodeling factors like CHD8 that are recruited to H3K4me chromatin are associated with a range of neurodevelopmental conditions. Intriguingly, mutations of H3K4me-specific lysine demethylases (KDMs) are also associated with autism and intellectual disability. As KDMs have multiple mechanistic functions, we recently examined neurodevelopmental phenotypes of mice that specifically lack KDM5B demethylase activity to determine the role of demethylation in brain development.

I will present our characterization of the behavioral, structural, and molecular phenotypes of these mice, as well as an identification of a neurodevelopmental signaling pathway that can be targeted pharmaceutically to rescue some of the neurodevelopmental phenotypes associated with KDM5B deficiency.

Together, our findings show that dysregulation of H3K4me can give rise to autism-like and learning and memory phenotypes in mice and that some of these phenotypes can be rescued postnatally.