Bringing people and ideas together to fund, conduct, and share transformative science.
Our grants advance knowledge and strengthen connections between science and society.
Discover the latest news, research, and updates.
We convene scientists, mathematicians, and thinkers to share ideas and explore new questions.
Founded by Jim and Marilyn Simons, we’re a private philanthropy advancing mathematics and basic science.
Work with us on the frontier of basic science research.
The Flatiron Institute is a research center that uses computational science to advance fields like physics, biology, and astronomy.
Search
Funded Work
2017
Pilot
SFARI Investigator
Advances in genetics have defined a large number of high-confidence risk genes that are mutated in autism spectrum disorder (ASD). Many of these ASD genes encode epigenetic modifiers that regulate gene expression in the developing brain. However, how mutation of these genes leads to ASD is not well understood.
Harrison Gabel and his colleagues at Washington University in St. Louis are exploring how disruption of one epigenetic mechanism, DNA methylation, can contribute to ASD. Building on recent genetic studies that have identified ASD-associated mutations in the DNMT3A DNA methyltransferase, they will establish a mouse model of DNMT3A disruption in ASD. They will characterize the alterations in DNA methylation, gene expression and neuronal cell function that occur in the brains of these mice and examine how these disruptions can contribute to ASD-relevant behaviors.
Based on recent observations that DNMT3A deposits a unique form of non-CG DNA methylation across the genome of neurons during development, these studies will test the hypothesis that DNMT3A mutations alter this brain-specific non-CG methylation to drive neural dysfunction. In parallel studies, Gabel and colleagues will characterize the molecular effects of specific DNMT3A missense mutations that have been identified in individuals with ASD. Through the analysis of these mutations in a neuronal cell culture system in vitro and the generation of mice carrying precise disease-associated mutations in vivo, Gabel’s team will determine which aspects of DNMT3A function are inactivated across all ASD-associated DNMT3A mutations. These planned experiments will isolate the core disruption of DNMT3A that must occur to drive ASD pathology.
Taken together, these studies will provide new models for the study of the molecular etiology of ASD caused by mutations in DNMT3A. In addition, this work will begin to define convergent etiology that is shared between autism and related neurodevelopmental disorders.