Defining the Role of HDAC3 Deacetylation and Decrotonylation in T Cells

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Presentation Time: 11:00 AM - 11:15 AM
Abstract ID: 4997 - B

Presenting Author:
Kodi Martinez , Graduate student at Mayo Clin. Grad. Sch. of Biomed. Sci.

Abstract:

Generation of T cells requires dynamic epigenetic alteration of histones to control gene expression at each developmental stage. The Class I deacetylases HDAC1, HDAC2, and HDAC3 have been shown to have decrotonylase activity and deacetylase activity, but the relative importance of deacetylation as compared to decrotonylation in T cells is not known. Recently, a mutation was identified in HDAC3 that eradicated deacetylase activity but retained decrotonylase activity (“VRPP”). We generated a novel mouse model with Cre-mediated deletion of endogenous HDAC3 and linked re-expression of HDAC3 VRPP. Similar to CD2icre HDAC3 cKO mice, HDAC3 VRPP mice have a block in positive selection due to failure to down regulate RORγt and decreased DP cell survival due to increased expression of P2RX7, demonstrating that HDAC3 deacetylase activity is important for these functions. In addition, although fewer T cells are produced in HDAC3 VRPP mice, CD4⁺ lineage commitment is restored. Strikingly, this mouse does not develop spontaneous colitis even up to one year of age, although T cell development is still impaired. Thus, there are different roles for HDAC3 deacetylation activity during T cell development which are made evident in HDAC3 VRPP mice.