Abstract 108: Reactivation of Myc Transcription in the Heart Unlocks its Proliferative Capacity

Abstract

It is unclear why some tissues are refractory to the mitogenic effects of the pleiotropic transcription factor Myc, even when its expression is deregulated. We have developed an in vivo model permitting determination of the early transcriptional consequences of Myc activation across all tissues of an adult mouse. Myc activation induces rapid transcriptional responses, followed by cell proliferation in some, but not all, organs. Despite such disparities in proliferative response, Myc bound DNA at open promotor and enhancer elements, in representative responsive (liver) and non-responsive (heart) tissues, but failed to induce a robust transcriptional and proliferative response in the heart. Therefore, the determinants of transcriptional responsiveness are distinct from chromatin state and DNA binding by Myc. Using heart as an exemplar of a non-responsive tissue, we show that Myc-driven transcription may be re-engaged in mature cardiomyocytes by elevating levels of the P-TEFb, instating a profound proliferative response to Myc. These data indicate that the cardiac epigenomic architecture does not preclude Myc binding to E-boxes; rather, it is the inability of Myc to drive transcriptional output from Myc target genes that thwarts cardiomyocyte proliferation. Hence, P-TEFb activity is a key limiting determinant of whether or not an individual tissue is permissive for Myc transcriptional activation and mitogenesis. These data provide not only a greater understanding of how Myc transcriptional activity is determined in cellular contexts, they also indicate that modification of the expression levels of the transcriptional co-factor P-TEFb could be a means through which adult cardiomyocytes could be regenerated for the treatment of heart conditions.