Author(s): Jamy Peng, St. Jude Children’s Research Hospital; Yurika Matsui, St. Jude Children’s Research Hospital; Hongfeng Chen, St. Jude Children’s Research Hospital; Beisi Xu, St. Jude Children’s Research Hospital //

ABSTRACT: Mutations in enzymes that modify lysine 27 in histone H3 (H3K27) are strongly associated with developmental disorders including Weaver syndrome, Kabuki syndrome, and Rubinstein-Taybi syndrome.  These enzymes deposit methylation (PRC2; Weaver), remove methylation (UTX; Kabuki), or deposit acetylation (CREBBP or EP300; Rubinstein-Taybi) on H3K27.  H3K27 modifications are linked to suppressed or active expression of developmental regulators, suggesting that dysfunction in H3K27 modifiers leads to deregulated genetic programs that cause these developmental disorders.  As the disorders present striking brain phenotypes, my group studies H3K27 modifiers in human brain organoids and the mouse embryonic brain.  We have been focused on identifying new players in PRC2 and UTX networks in neural stem cells.  We recently showed that the nucleoprotein Ybx1 binds to PRC2, influencing PRC2 localization and reducing H3K27 trimethylation levels genome-wide in embryonic neural stem cells.  The PRC2–Ybx1 interaction regulates spatiotemporal genetic programs in the developing brain.  In follow-up studies, we found that Ybx1 binds neurogenic enhancers and is required for maintaining H3K27 acetylation levels and expression of the enhancer target genes.  CUT&RUN followed by immunoprecipitation revealed that Ybx1 proteins co-occupy chromatin regions with either H3K27 methylation or acetylation.  We are using mouse knockout of Ybx1, PRC2, Utx, Cbp, and p300 to interrogate a synergistic or antagonistic interaction of Ybx1 with H3K27 modifiers in regulating embryonic brain development.  We hypothesize that Ybx1 exerts dualistic influences over H3K27 methylation and acetylation on chromatin to regulate gene expression.  This coordination of H3K27 modifiers has a broader implication about the function and regulation of chromatin modifiers (and likely Polycomb Group and Trithorax Group proteins) over developmental genetic programs.  By attending this workshop, we want to share our findings and find potential collaborators to work on the basic research program or model developmental disorders.

Source of Funding: American Lebanese Syrian Associated Charities, American Cancer Society (132096-RSG-18-032-01-DDC), and NIH (1R01GM134358-01)