UBR7 Is a Novel Chromatin-Associated Protein Associated With Autism

We have identified UBR7 as a novel chromatin-associated protein. An inherited mutation of UBR7 (N124S) is associated with a family with autism (ASD). Like the mutation in UBR7, many mutations associated with ASD are private mutations. Therefore, understanding the function of genes like UBR7 is essential to determining the underlying mechanisms of ASD. UBR7 is a member of a family of proteins that contain a UBR-box usually associated with N-end rule degradation of proteins. However, UBR7 does not appear to function in this pathway. The function of UBR7 is unknown. UBR7 is the only family member containing a PHD domain. We have demonstrated that UBR7 binds to H3K9me3 modified H3.1 N-terminal tails in a PHD-dependent manner. The N124S mutation alters protein stability and prevents binding to H3.1 tails. iPSC-derived neural progenitor cells (NPCs) lacking UBR7 expression are viable. Loss of UBR7 results in an increase in the rate of NPC differentiation. We are performing a genome-wide CRISPR screen to identify genes that genetically interact with UBR7. We are utilizing zebrafish as a model to determine the physiological role of UBR7 in vertebrate development. We are performing in situ hybridization to determine when and where the two zebrafish paralogs of Ubr7, zUbr7a and zUbr7b, are expressed. We will knock-out zUBR7a and zUBR7b using the CRISPR/Cas9 system to evaluate the effects of zUbr7a/b loss on vertebrate development.