Nucleoporin 107, 62 and 153 mediate Kcnq1ot1 imprinted domain regulation in extraembryonic endoderm stem cells.

Genomic imprinting is a phenomenon that restricts transcription to predominantly one parental allele. How this transcriptional duality is regulated is poorly understood. Here we perform an RNA interference screen for epigenetic factors involved in paternal allelic silencing at the Kcnq1ot1 imprinted domain in mouse extraembryonic endoderm stem cells. Multiple factors are identified, including nucleoporin 107 (NUP107). To determine NUP107's role and specificity in Kcnq1ot1 imprinted domain regulation, we deplete Nup107, as well as Nup62, Nup98/96 and Nup153. Nup107, Nup62 and Nup153, but not Nup98/96 depletion, reduce Kcnq1ot1 noncoding RNA volume, displace the Kcnq1ot1 domain from the nuclear periphery, reactivate a subset of normally silent paternal alleles in the domain, alter histone modifications with concomitant changes in KMT2A, EZH2 and EHMT2 occupancy, as well as reduce cohesin interactions at the Kcnq1ot1 imprinting control region. Our results establish an important role for specific nucleoporins in mediating Kcnq1ot1 imprinted domain regulation.