Modulation of chromatin dynamics to promote transplant survival

Methodist Hospital Research Institute, Houston TX

Investigators

Abstract

Project Summary Rejection remains a major hurdle to long-term transplant survival, in which Teff cells are prominently involved. We surmise that besides signals from the TCR, costimulatory and cytokine receptors, targeting the “T cell epigenome” downstream of T cell activation may represent novel therapeutic opportunities in the induction of transplant tolerance. Now we have new preliminary data showing that the chromatin in Teff cells are highly compartmentalized, in that “super enhancers” at accessible chromatin regions appear to control a Teff cell fate by recruiting a chromatin reader called BRD4. We then developed a Brd4-floxed mice and showed that conditional deletion of Brd4 in T cells completely abrogated the lethal autoimmune phenotype in Scurfy mice and produced long-term allograft survival in Brd4f/fCd4-Cre mice. Thus, dissecting mechanistically how BRD4 epigenetically regulates Teff cells and transplant survival is the central goal of this proposal. Our working hypothesis is that BRD4 occupancy at the accessible chromatin regions locks active chromatin modules in an accessible state or triggers reorganization of “super enhancers” into transcriptionally hyper-active “hotspots” to drive a Teff cell fate. We proposed 3 Aims in this proposal to test this hypothesis. Aim 1 is to determine whether BRD4 locks “active” chromatin modules in an accessible state, allowing the formation of 3D chromatin configurations to specify a Teff cell fate, and Aim 2 is to examine whether BRD4 enables stable SE “hotspots”, allowing Teff cells to establish essential features of Teff profiles. Aim 3 is to test whether therapeutically targeting BRD4 enables long-term allograft survival in a heart transplant model. We believe that the proposed studies will uncover new insights and open new therapeutic opportunities in transplantation. The animal models, tools, and cutting-edge technologies we have developed in the lab put us in a unique position to carry out the proposed studies.