The function of TWIST1 acetylation in cell fate and tissue development

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Abstract Craniofacial disorders are the second most common congenital birth defects, while pediatric cancers are the leading cause of death in children. These anomalies arise from a disruption in regulating neural tube (NT) and cranial neural crest cell (CNCC) development. Despite the high prevalence, significant gaps remain in our knowledge of the genetic risk factors and the underlying mechanisms that lead to these disorders. We have recently identified a novel function of Twist1 in the neural tube and CNCC fate transition. Our recent findings showed that Twist1 is involved in cell shape changes during NT closure and suppresses epithelial genes during the epithelial-to-mesenchymal transition (EMT) of pre-migratory CNCCs to become migratory mesenchymal cells. In addition, our supporting data indicates that TWIST1 is acetylated at K73; K76 in cancer cells, and the di-acetylated K73Ac;K76Ac enables TWIST1 to interact with histone acetyl-transferase factors, BRD8, p400, EPC1, and TIP60, which are members of the NuA4 complex, in cancer cells. To follow up on our findings, the Xu lab at Baylor College of Medicine (BCM) will establish a new collaboration with Fakhouri lab at UTHealth School of Dentistry to determine the novel significance of TWIST1 acetylation in the development and CNCC- derived tumor formation. For this collaborative project, we hypothesize that TWIST1 acetylation is necessary to dictate the interaction with chromatin modifying factors to control cell fate determination during craniofacial development and CNCC-derived tissue differentiation. To test this high-risk, high-reward hypothesis, we will generate acetylated-incompetent (K73A; K76A), acetylated-mimic (K73Q; K76Q), and deacetylated- mimic/incompetent (K73R; K76R) mouse lines and genetically-modified O9-1 CNCC lines with similar point- mutations. The phenotypical, histological, and cellular analyses of the mouse lines will assess the function of TWIST1 acetylation in tissue development and potentially CNCC-derived tumor formation. We will investigate TWIST1 acetylation and CNCC differentiation capacity in O9-1 stable lines. This project aims to: (1) Uncover the function of TWIST1 acetylation in craniofacial development and tumor formation, (2) Investigate the interaction between TWIST1 and NuA4 chromatin modifying complex and their involvement in CNCC differentiation capacity. We will determine the impact of Twist1 acetylated-incompetent (K73A/R; K76A/R) and acetylated-mimic (K73A; K76A) mouse lines on NT closure, fate transition in pre-migratory CNCCs, and CNCC- derived tumor formation. We will examine in O9-1 CNCC line the significance of interaction with the members of NuA4 chromatin-modifying complex, and O9-1 CNCC migratory and differentiation capacity. This project will provide a tremendous opportunity to establish a cross-disciplinary collaboration that will leverage our complementary strengths in mouse genetics, craniofacial development, and cancer biology.