- Awarded: 2020
- Award Type: Research
- Award #: 703333
Extensive genetic evidence implicates mutations in genes that encode subunits of the BAF chromatin remodeling complex (e.g., ACTL6B, ARID1B, ARID2, ATRX, BICRA, SMARCA2, SMARCA4 and SMARCC2) as significant risk factors for autism spectrum disorder (ASD) and other neurodevelopmental conditions. Furthermore, the deletion of specific BAF subunits has been shown to affect dendritic outgrowth and more severe disruption of the BAF complex results in pronounced defects in chromatin regulation and forebrain development. However, the specific mechanisms by which impairment of the neuronal form of the BAF complex (nBAF) contributes to ASD pathophysiology remain unclear.
In the course of studies aimed at investigating stimulus-responsive gene expression programs mediated by the immediate-early gene transcription factors Fos/Jun (AP-1), Michael Greenberg and colleagues found that the BAF complex acts as a major mediator of stimulus-driven AP-1 transcriptional activity in response to activation of the Ras/MAPK signaling pathway in non-neuronal cell types1. These findings are striking in light of the recent observation by his laboratory and others that neuronal activity drives acute local increases in chromatin accessibility at AP-1-bound neuronal enhancer elements2. Moreover, AP-1-binding sequence motifs were recently found to be enriched at cortical cis-regulatory elements that show altered activity in ASD3.
In the current project, Greenberg proposes to test the hypothesis that the nBAF complex mediates activity-dependent AP-1 signaling in neurons and that defects in this response contribute to the effects of nBAF mutations in ASD. These studies have the potential to link nBAF to a larger constellation of ASD susceptibility loci associated with altered Ras/MAPK signaling.
Specifically, Greenberg and colleagues will seek to determine whether neuronal activity-responsive chromatin remodeling is impaired in a mouse model of Arid1b haploinsufficiency. In addition, the researchers will investigate the contribution of the nBAF complex to neuronal activity-dependent gene expression programs in human pluripotent stem cell-derived glutamatergic neurons.
Taken together, the proposed experiments will provide a better understanding of BAF function and yield insight into the etiology of a range of syndromic and non-syndromic ASDs.