Several transcriptional regulator genes are strongly associated with an increased risk of autism spectrum disorder (ASD). Of these, ADNP and POGZ are two chromatin regulators with similarities in their structure and function. ADNP and POGZ both encode proteins that bind HP1, a scaffolding protein of heterochromatin. Previous work has shown that ADNP and POGZ share genomic targets in mouse and human tissue, including numerous neuronal gene regulatory elements¹. The majority of individuals with POGZ and ADNP mutations present with both ASD and intellectual disability.

In the current project, Eirene Markenscoff-Papadimitriou and her colleagues at Cornell University plan to use heterozygote knockout mouse models of Pogz and Adnp, as well as induced pluripotent stem cell (iPSC)-derived neurons lacking POGZ and ADNP, to examine the impact of loss-of-function of these two genes on cortical gene expression and chromatin state. Techniques to be used include single-cell RNA-seq (RNA sequencing), ATAC-seq (assay for transposase-accessible chromatin sequencing) and circuit tracing.

One of the challenges of studying a heterogeneous disorder like ASD is finding convergent processes underlying the pathogenesis of the disorder from different gene mutations. Another challenge is that many ASD risk genes, including POGZ and ADNP, are expressed ubiquitously in the developing brain with no apparent cell-type specificity. Markenscoff-Papadimitriou and her team plan to identify distal enhancers commonly dysregulated by mutations in POGZ and ADNP. One candidate enhancer already identified is an intronic element that regulates the high- confidence ASD risk gene SLC6A1¹. Analyzing enhancer transgenic mice for Pogz– and Adnp-regulated enhancers will point to the cell types and circuits where developmental gene expression may be commonly impacted by mutations in these two genes.

1. Markenscoff-Papdimitriou E. et al. Cell Rep. 37, 110089 (2021) PubMed