Role of Class IIa HDACs HDAC4 and HDAC7 in Pathogenic Th17 Cell Development and Colitis

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PROJECT SUMMARY Th17 cells play important roles in adaptive immunity and autoimmune diseases. In normal physiological conditions, Th17 cells produce IL-17A and IL-17F to protect the mucosa from bacterial and fungal infections. Dysregulation of Th17 cells, however, is responsible for inflammatory bowel diseases, multiple sclerosis and rheumatoid arthritis. Differentiation of Th17 cell lineage has been investigated intensively and has yielded significant results. The cooperation of key transcriptional factors such as Irf4, Batf, Stat3 together with lineage- specific regulator RorgT defines the transcriptional program and function of Th17 cells. These regulatory networks are induced by IL-6 and TGF-b1, and further IL-23 signaling pathways promote the development of pathogenic Th17 cells. To identify Th17-specific regulators, we recently conducted comprehensive ChIP-seq and RNA-seq studies of Th17 cells and discovered Class IIa Hdacs Hdac4 and Hdac7 as candidates that are transcriptionally regulated by Stat3 and BET proteins. We further found that Hdac4 and Hdac7 co-localize with distinct transcription factors JunB and Bhlhe40 on cis-regulatory regions of genes, to activate Th17 pathogenic genes (Il23r, Tgfb3, Il22, Csf2) and repress regulatory gene (Il10), respectively, during pathogenic Th17 cell differentiation (IL-6+IL-23+IL-1b). However, we still have limited mechanistic understanding how Hdac4 and Hdac7 function distinctly in pathogenic Th17 cell development. It is also unclear how Hdac4 and Hdac7 facilitate Th17 pathogenicity through the regulation of Th17 cell maintenance and/or plasticity in colitis. We therefore aim to delineate the role of Hdac4 and Hdac7 in Th17 cell-mediated inflammation, and establish the feasibility of pharmacological inhibition of Hdac4 and/or Hdac7 as a novel therapeutic strategy to treat Th17- related colitis.