Epigenetic Coactivation of <b><i>MAGEA6</i></b> and <b><i>CT-GABRA3</i></b> Defines Orientation of a Segmental Duplication in the Human X Chromosome

Abstract

The human genome harbors many duplicated segments, which sometimes show very high sequence identity. This may complicate assignment during genome assembly. One such example is in Xq28, where the arrangement of 2 recently duplicated segments varies between genome assembly versions. The duplicated segments comprise highly similar genes, including <i>MAGEA3</i> and <i>MAGEA6</i>, which display specific expression in testicular germline cells, and also become aberrantly activated in a variety of tumors. Recently, a new gene was identified, <i>CT-GABRA3</i>, the transcription of which initiates inside the segmental duplication but extends far outside. According to the latest genome annotation, <i>CT- GABRA3</i> starts near <i>MAGEA3</i>, with which it shares a bidirectional promoter. In an earlier annotation, however, the duplicated segment was positioned in the opposite orientation, and <i>CT-GABRA3</i> was instead coupled with <i>MAGEA6</i>. To resolve this discrepancy, and based on the contention that genes connected by a bidirectional promoter are almost always co-expressed, we decided to compare the expression profiles of <i>CT-GABRA3</i>,<i> MAGEA3</i>, and <i>MAGEA6</i>. We found that in tumor tissues and cell lines of different origins, the expression of <i>CT-GABRA3</i> was better correlated with that of <i>MAGEA6</i>. Moreover, in a cellular model of experimental induction with a DNA demethylation agent, activation <i>CT-GABRA3</i> was associated with that of <i>MAGEA6</i>, but not with that of <i>MAGEA3</i>. Together these results support a connection between <i>CT-GABRA3</i> and <i>MAGEA6</i> and illustrate how promoter-sharing genes can be exploited to resolve genome assembly uncertainties.