Dynamic Regulation of Epidermal Differentiation Genes by Cell-State-Specific PBAF Interactome

About This Grant

Dynamic Regulation of Epidermal Differentiation Genes by Cell-State-Specific PBAF Interactome Epidermal homeostasis requires cell-state-specific regulation of differentiation genes, maintaining repression in progenitors while ensuring timely activation in the terminal differentiation process to establish barrier function. Dysregulation of differentiation genes contributes to prevalent skin disorders such as psoriasis, eczema, and cutaneous squamous cell carcinoma. The molecular mechanisms governing the transition between repression and activation for differentiation genes remain incompletely understood, limiting the development of new targeted therapeutic strategies. We recently discovered that the PBAF chromatin remodeling complex plays dual roles in epidermal differentiation regulation: it functions as a repressor in the progenitors, but switches to an activator in the terminal differentiation process. To begin unraveling the molecular mechanism underlying PBAF’s functional switch, we discovered that PBAF’s protein interactome, rather than its genomic binding sites, undergoes drastic changes between the progenitor and the differentiation state. Using a targeted genetic screen, we identified the E3 SUMO ligase PIAS1 as a crucial PBAF interactor for repressing differentiation. Building on these findings, we will elucidate the mechanisms underlying PBAF’s functional switch from repressor to activator in differentiation regulation, using PBAF-PIAS1 interaction as the focal point to understand the contributions from other interacting proteins. First, we will define the upstream regulatory mechanisms controlling PIAS1-PBAF association and dissociation. Second, we will determine the downstream impact of PIAS1-PBAF interaction in epidermal differentiation regulation. We hypothesize that PIAS1’s protein stability and association with PBAF is regulated by ubiquitination, and PIAS1’s SUMOylation activity directly impacts the recruitment of repressors versus activators to differentiation genes. Leveraging my lab’s expertise in functional genomics, proteomics, and epidermal tissue models, this study will dissect the molecular pathways modulating differentiation gene repression versus activation through the PBAF interactome. By elucidating both the upstream mechanisms governing the PBAF interactome and the downstream impacts on differentiation dynamics, this work will significantly advance our understanding of epidermal differentiation regulation. Specifically, it will shed light on several underexplored areas, including the identification of novel differentiation regulators and the roles of ubiquitination and SUMOylation in this process. By uncovering novel regulators and molecular mechanisms governing epidermal differentiation, our findings can inform new therapeutic strategies for treating disorders characterized by epidermal differentiation dysregulation, aligning with NIAMS’s mission to advance the understanding and treatment of skin diseases.