Loss-of-function mutations in repressive chromatin modifying enzymes such as euchromatic histone methyltransferase 1 (EHMT1) are frequent causes of neurodevelopmental conditions, including autism spectrum disorder (ASD). How early embryonic mutations in EHMT1 result in functional changes in mature neurons remains poorly understood.
Based on his lab’s recent studies on chromatin and transcriptional remodeling driven by EHMT11, Matthias Stadtfeld proposes that reduced activity levels of this enzyme during neurogenesis result in stage-specific and accumulative molecular damage that cannot be effectively reversed after neuronal differentiation is completed. This would have considerable ramifications for the design of effective therapies.
Stadtfeld and colleagues plan to test this hypothesis by engineering multipurpose degron alleles in human embryonic stem cells that allow controlled EHMT1 degradation, unbiased immunoprecipitation and visualization of the transcriptional kinetics. The research team plans to use directed differentiation of these cells to create a high-resolution, high-confidence reference map for the molecular activity of EHMT1 during human neurogenesis. They will then model EHMT1 deficiency in their experimentally tractable setting by determining genome-wide changes in RNA abundance and repressive chromatin marks in different cell types with pathologically reduced EHMT1 levels. These experiments will help link molecular changes to specific functional properties of mature neurons that have been associated with ASD. In subsequent studies, they plan to determine the degree to which molecular and cellular phenotypes that were introduced by reduced EHMT1 levels at early developmental stages can be reversed by later restoration of physiological levels of this enzyme.
The systematic assessment of the nature and reversibility of molecular alterations caused by EHMT1 deficiency will generate mechanistic insight into the function of an important regulator of human neurogenesis. Such findings are likely to have important implications for the development of novel therapeutic interventions for ASD. The integration of degron technology into directed differentiation regimens will also help to establish a widely applicable experimental paradigm for the study of ASD risk genes.
- Leveraging a high-throughput CRISPR screen to assess convergent neurogenesis phenotypes across autism risk genes
- Cellular and molecular analysis of Setd2 function during cortical neurogenesis
- Assessing how the autism risk gene ASXL3 regulates cortical neuronal fate
- Mapping ASD regulatory networks at cellular resolution in neurodevelopment