Abstract
Much progress has been made in understanding the important cis-mediated controls on mouse TCRα gene function, including identification of the Eα enhancer and TCRα locus control region (LCR). Nevertheless, previous data have suggested that other cis-regulatory elements may reside in the locus outside of the Eα/LCR. Based on prior findings, we hypothesized the existence of gene regulatory elements in a 3.9-kb region 5’ of the Cα exons. Using DNase hypersensitivity assays and TCRα BAC reporter transgenes in mice, we detected gene regulatory activity within this 3.9-kb region. This region is active in both thymic and peripheral T cells, and selectively affects upstream, but not downstream, gene expression. Together, these data indicate the existence of a novel cis-acting regulatory complex that contributes to TCRα transgene expression in vivo. The active chromatin sites we discovered within this region would remain in the locus after TCRα gene rearrangement, and thus may contribute to endogenous TCRα gene activity, particularly in peripheral T cells, where the Eα element has been found to be inactive.
Highlights
The functional rearrangement and expression of the TCRα gene during T cell development results in cell surface αß TCR complex emergence
We report the presence of an array of DNase I hypersensitive sites (HS) in a region of the mouse TCRα locus that ranges from the Jα2 segment to the Cα1 exon
The most prominent of these HS is proximal to the Jα1 segment (HS-J1), which is located near the center of the HS array
Summary
The functional rearrangement and expression of the TCRα gene during T cell development results in cell surface αß TCR complex emergence. The region of HS1 (which contains the Eα transcriptional enhancer [5]) and the HS1 prime (HS1’) element [6] is critical for normal TCRα gene rearrangement [7] This region very strongly increases transcription levels in T cells in vivo [6, 7], likely via epigenetic regulation of chromatin states [8, 9]. While the importance of the HS1/HS1’ DNA region to the function of the TCRα locus is indisputable, limited TCRα gene recombination is observed in its absence This is accompanied by TCRα transcription levels adequate to support maintenance of a peripheral T cell population
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