PROJECT ABSTRACT Epigenetic factors are genes that encode proteins that can affect spatial organization of DNA and the accessibility of genetic regions to transcriptional machinery, thereby regulating cell-type specific transcription. Pathogenic mutations in established epigenes are highly enriched in children with pediatric syndromic disorders, often with symptoms that affect multiple organ systems, such as the brain, heart, gastrointestinal tract, bone, eye and kidneys. The associated symptoms of intellectual disability, developmental delays, autism, diarrhea and congenital heart defects vary in severity between individuals. The onset of these syndromes during early childhood suggest that many of these epigenetic factors are critical to early developmental processes and cell- fate transitions. Despite our improved diagnostic ability with exome sequencing, the mechanistic link between epigenetic factor mutations and the direct mechanisms by which they disrupt mammalian developmental processes remains unknown. Histone acetyltransferases (HATs) are genes that acetylate lysine (K) residues and represent a common mechanism for controlling DNA accessibility to the transcriptional machinery. Here, we study protein-truncating variants in two HATs: Lysine (K), Acetyl transferase 6A and 6B (KAT6A and KAT6B), which cause Arboleda-Tham Syndrome (ARTHS) and Genitopatellar Syndrome (GPS) or Say-Barber-Biesecker- Young Syndrome (SBBYS), respectively. Our goal is to develop and validate transgenic mouse models harboring patient-specific mutations in these genes to establish the differential roles of these epigenetic factors on cell specification during development driving the distinct syndromes.

PROJECT NARRATIVE Epigenes are genes that encode proteins that can affect chromatin’s spatial organization and regulate cell-type specific transcription. The role of these genes in programming early developmental cell-fate transitions can be best modeled in complex systems such as mouse development. We developed mouse models of epigene mutations in the histone acetyltransferase genes in order to understand the multi-organ effects of KAT6A and KAT6B across early development.