2431-P: Identification of a KAT8–WDR5 Interaction in Adipocytes

Introduction and Objective: Lysine Acetyltransferase 8 (KAT8) is a histone acetyltransferase that regulates transcription through acetylation of histone H4 lysine 16 and functions within multi-protein transcriptional complexes. We have shown that adipocyte-specific deletion of KAT8 in mice decreases fat mass and induces insulin resistance, and that KAT8 protein, but not mRNA, expression in adipose tissue responds dynamically to nutritional state, highlighting its relevance to energy metabolism. The objective of this study was to identify KAT8-associated protein complexes in adipocytes and define candidate regulatory partners relevant to adipocyte function. Methods: To examine KAT8 function in adipocytes, immunoprecipitation (IP) was performed in mature 3T3-L1 adipocytes to identify KAT8-associated proteins under endogenous conditions. Publicly available human and mouse adipose tissue transcriptomic datasets were analyzed to assess expression of KAT8 and components of two known KAT8-associated complexes, the Non-Specific Lethal (NSL) and Male-Specific Lethal (MSL) complexes, in adipose tissue. Quantitative mass spectrometry approaches are being employed to define the adipocyte-specific KAT8 interactome. Results: IP identified WD Repeat Domain 5 (WDR5), a scaffold protein of the NSL complex, as a KAT8-associated protein in adipocytes. Transcriptomic analyses demonstrated expression of KAT8, WDR5, and additional NSL/MSL complex components in adipose tissue. Conclusion: Our findings demonstrate that KAT8 and WDR5 form a protein complex in adipocytes, highlighting the potential regulatory importance of the NSL complex in adipocyte biology. Ongoing proteomic analyses, together with targeted siRNA-mediated knockdown of WDR5, are being used to examine the functional significance of this interaction in adipocyte metabolism and the pathogenesis of metabolic disorders such as insulin resistance and type 2 diabetes. Disclosure L.G. Yoo: None. A.J. Richard: None. J. Stephens: None. Funding R01DK135266