Loss of an Igκ Gene Enhancer in Mature B Cells Results in Rapid Gene Silencing and Partial Reversible Dedifferentiation

Abstract

ABSTRACT We address here whether there is cellular memory of a transcriptional enhancer once it has served its purpose to establish an active chromatin state. We have previously shown that the mouse Igκ gene's downstream enhancers, E3′ and Ed, are essential but play redundant roles for establishing transcriptional activity in the locus during B cell development. To determine whether these enhancers are also necessary for the maintenance of transcriptional activity, we conditionally deleted E3′ in mature B cells that possessed Ed −/− alleles. Upon E3′ deletion, the locus became rapidly silenced and lost positive histone epigenetic marks, and the mature B cells partially dedifferentiated, induced RAG-1 and -2 along with certain other pro-B cell makers, and then redifferentiated after triggering Igλ gene rearrangements. We conclude that the Igκ gene's downstream enhancers are essential for both the establishment and maintenance of transcriptional activity and that there is no cellular memory of previous transcriptional activity in this locus. Furthermore, upon enhancer loss, the mature B cells unexpectedly underwent reversible retrograde differentiation. This result establishes that receptor editing can occur in mature B cells and raises the possibility that this may provide a tolerance mechanism for eliminating autoreactive B cells in the periphery.