Enhancer-driven chromatin interactions during development promote escape from silencing by a long non-coding RNA

We show that Kcnq1 transitions from monoallelic to biallelic expression during mid gestation in the developing heart. This transition is not associated with the loss of methylation on the Kcnq1 promoter. However, by exploiting chromosome conformation capture (3C) technology, we find tissue-specific and stage-specific chromatin loops between the Kcnq1 promoter and newly identified DNA regulatory elements. These regulatory elements showed in vitro activity in a luciferase assay and in vivo activity in transgenic embryos.By exploring the spatial organization of the Kcnq1 locus, our results reveal a novel mechanism by which local activation of genes can override the regional silencing effects of non-coding RNAs.Genomic imprinting is a transcriptional regulatory mechanism that results in parental-specific gene expression. Over the past two decades, many mechanistic insights have emerged from the study of such loci as the H19/Igf2 domain [1]. However, most imprinted loci are much more complex and exhibit tissue-specific as well as stage-specific imprinting. Many significant questions remain concerning the regulatory mechanisms governing such extended domains. For example, how genes that are monoallelic can coexist interspersed with others that exhibit partial or full biallelic expression is still not understood. The prevalent hypotheses for the appearance of imprinting imply that, although advantageous in some respects, it imposed a burden on bystander genes that came under its influence. Thus, it is likely that mechanisms emerged to bypass the effects of allelic silencing.The Kcnq1 domain consists of at least ten genes exhibiting parental allele-specific expression [2], interspersed with five genes that are biallelically expressed. The key regulatory element, KvDMR, is a CG-rich promoter for a long, non-coding RNA [3]. The paternal copy of the KvDMR is hypomethylated and active, resulting in production of a 90-kb non-coding RNA (ncRNA), Kcnq1ot1. Transcription of the Kcn