Developmental Switch in the Transcriptional Activity of a Long-Range Regulatory Element

Eukaryotic gene expression is often controlled by distant regulatory elements. In developing B lymphocytes, transcription is associated with V(D)J recombination at immunoglobulin loci. This process is regulated by remote cis-acting elements. At the immunoglobulin heavy chain (IgH) locus, the 3' regulatory region (3'RR) promotes transcription in mature B cells. This led to the notion that the 3'RR orchestrates the IgH locus activity at late stages of B cell maturation only. However, long-range interactions involving the 3'RR were detected in early B cells, but the functional consequences of these interactions were unknown. Here we show that not only does the 3'RR affect transcription at distant sites within the IgH variable region but also it conveys a transcriptional silencing activity on both sense and antisense transcription. The 3'RR-mediated silencing activity is switched off upon completion of VH-DJH recombination. Our findings reveal a developmentally controlled, stage-dependent shift in the transcriptional activity of a master regulatory element.