Mechanism of lymphocyte-specific inactivation of RAG-2 intragenic promoter of NWC: implications for epigenetic control of RAG locus.

NWC, third evolutionarily conserved gene within RAG locus is transcribed at high level in all cells except mature T and B lymphocytes and their RAG negative progenitors. It is so, because in lymphocytes expression of NWC is regulated by RAG-1 promoter, while in other cells it is controlled by RAG-2 intragenic promoter which in T and B lymphocytes is silent. Here we show that lymphocyte-specific inactivation of NWC promoter is caused by CpG island hypermethylation accompanied by site-specific blocking of chromatin accessibility, which in contrast to RAG promoters, is not accompanied by expected posttranslational modifications of histone H3. These results indicate that accessibility of NWC promoter and RAG promoters to trans-acting factors is regulated by different epigenetic mechanisms. The implications of our findings for understanding mechanisms regulating transcription within RAG/NWC locus in different cells are discussed and the model of epigenetic control of this locus is proposed.