A large number of mutations in chromatin regulatory proteins have been observed in autism spectrum disorders (ASDs). However, the molecular mechanisms through which many mutations contribute to the condition is unknown. A detailed understanding of these mechanisms and identification of the downstream consequences on gene-expression programs will be key to understanding etiology and uncovering new therapeutic options for ASDs.
Kavitha Sarma and colleagues have recently discovered that many chromatin regulators that are mutated in ASDs also function at chromatin structures called R-loops. This finding implicates R-loops as a new epigenetic mechanism for the development of numerous ASDs. R-loops are abundant, RNA-containing chromatin structures that have the potential to impact gene expression and change 3-D genome organization. Depletion of ASD-related R-loop regulators including CHD2, DHX30 and ADNP results in a global increase in R-loop levels. These data suggest that aberrant gene expression programs can arise in ASD through the anomalous accumulation of cellular R-loops.
Using genetically engineered human neural progenitor cells that can be differentiated into cortical neurons, Sarma and colleagues propose to 1) identify the genomic locations that accrue R-loops in response to reduced CHD2 and DHX30 levels, 2) examine how R-loop alterations impact neuronal gene expression programs and 3) test if genetic and chemical perturbation of R-loops can restore normal transcription outcomes in neurons. These studies will establish R-loops as a molecular driver of the deregulated gene expression in ASDs.
- Leveraging a high-throughput CRISPR screen to assess convergent neurogenesis phenotypes across autism risk genes
- Mapping ASD regulatory networks at cellular resolution in neurodevelopment
- Elucidating the role of chromatin-modifying complexes in autism spectrum disorder
- Building phenotypic maps based on neuronal activity and transcriptional profiles in human cell models of syndromic forms of ASD