The lysine acetyltransferase KAT6A epigenetically facilitates glucose metabolic programming and CD4+ T-cell responses in autoimmunity

Epigenetic programs are pivotal regulators of effector CD4+ T cells and determine the fate of many autoimmune disorders. Here, we show that the acetyltransferase KAT6A acts as a novel regulator of glucose metabolism that is required for the proliferation and effector functions of CD4+ T cells in autoimmunity. Clinical analysis shows that KAT6A in CD4+ T cells is linked to the progression of autoimmune Sjogren's syndrome (SS) . Conditional knockout of KAT6A inhibits the proliferation and Th1/Th17 effector functions of CD4+ T cells both in vitro and that KAT6A-cKO CD4+T cells are less susceptible to induce adjuvant-immunized experimental autoimmune encephalomyelitis (EAE), autoimmune colitis and experimental SS. Combination of metabolomic, epigenetic and transcriptomic analyses show that KAT6A maintains abundant acetylation of H3K9ac and H3K27ac sites of several glycolytic genes, which in turn disrupts the transcriptional activation of MYC and HIF-1a, and potentiates the metabolic programming of glycolysis through its enzymatic amino acid points. Treatment with KAT6A small-molecule inhibitors in various autoimmune mice models shows high therapeutic value for targeting KAT6A to the treatment of autoimmune disorders. Our study reveals a critical role for KAT6A in autoimmunity via the epigenetic modification of glucose metabolic reprogramming and the effector response of CD4+ T cells. Overall design: The design of this experiment is to interrogate the role of Lysince acetyltransferase, namely Kat6a, to the H3K9ac and H3K27ac abundance at the chromosome of CD4+T cells. Briefly, CD4+T cells from littermate WT mice and conditional knock-out (Kat6afl/flCD4Cre+) mice were magnetically sorted, and then cultured in a 6-well plate at the concentration of 1*10^7 cells per plate. Cells were stimulated with anti-CD3/CD28 and cultured for 48 hrs. Then, ChIP-seq were performed and the following Raw data were produced.