The Runx3 distal transcript encodes an additional transcriptional activation domain

The runt family transcriptional regulator, Runx3, is upregulated during the differentiation of CD8 single-positive thymocytes and is expressed in peripheral CD8(+) T cells. Mice carrying targeted deletions in Runx3 have severe defects in the development and activation of CD8(+) T cells, resulting in decreased CD8(+) T-cell numbers, aberrant coexpression of CD4, and failure to expand CD8(+) effector cells after activation in vivo or in vitro. Expression of each of the three vertebrate runt family members, including Runx3, is controlled by two promoters that generate proteins with alternative N-terminal sequences. The longer N-terminal region of Runx3, expressed from the distal promoter, is highly conserved among family members and across species. We show that transcripts from the distal Runx3 promoter are selectively expressed in mature CD8(+) T cells and are upregulated upon activation. We show that the N-terminal region encoded by these transcripts carries an independent transcriptional activation domain. This domain can activate transcription in isolation, and contributes to the increased transcriptional activity observed with this isoform as compared to those expressed from the ancestral, proximal promoter. Together, these data suggest an important role for the additional N-terminal Runx3 activation domain in CD8(+) T-cell function.