Epigenetic regulation of transcription by long noncoding RNA

Recent evidence suggests that noncoding RNAs, which include both small and long noncoding RNAs, constitute a significant portion of the transcriptome in eukaryotic organisms. However, the functional significance of this widespread occurrence of noncoding RNAs, and in particular the long noncoding RNAs, in organismal development and differentiation is unclear. Emerging evidence indicate that a subset of long noncoding RNAs mediate their biological functions by using chromatin as a substrate to index the genetic information encoded in the genome. Our lab has been working towards understanding the functional role of long imprinted noncoding RNA Kcnq1ot1 and its promoter region in the parent of origin-specific gene expression in the mouse Cdkn1c/Kcnq1 imprinted domain at the distal end of the mouse chromosome 7 and its orthologous region in humans, known as Beckwith Wiedemann Syndrome (BWS) region, is located at the chromosome11p15.5. Cdkn1c/Kcnq1 domain is about one mega-base domain harbors 10-12 protein coding genes, exclusively expressed from the maternal chromosome and one paternally expressed long noncoding RNA Kcnq1ot1. Based on previous evidence, we suggested that the Kcnq1ot1 RNA, upon its transcription from the paternal chromosome, interacts with both DNA and chromatin remodelers and targets them to neighboring genes in cis to promote their transcriptional gene silencing. We have recently generated a transgenic mouse where Kcnq1ot1 RNA can be expressed conditionally at different developmental time points. We have documented that Kcnq1ot1 RNA establish reversible or irreversible silencing mechanisms in a gene-specific manner in the Cdkn1c/Kcnq1 domain. Kcnq1ot1 mediated gene-specific maintenance mechanisms operational at the Cdkn1C/Kcnq1 locus for tissue specific transcriptional gene silencing and activation will be discussed in the meeting.