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Many intergenic long noncoding RNA (lncRNA) loci regulate the expression of adjacent protein coding genes. Less clear is whether intergenic lncRNAs commonly regulate transcription by modulating chromatin at genomically distant loci. Here, we report both genomically local and distal RNA-dependent roles of Dali, a conserved central nervous system expressed intergenic lncRNA. Dali is transcribed downstream of the Pou3f3 transcription factor gene and its depletion disrupts the differentiation of neuroblastoma cells. Locally, Dali transcript regulates transcription of the Pou3f3 locus. Distally, it preferentially targets active promoters and regulates expression of neural differentiation genes, in part through physical association with the POU3F3 protein. Dali interacts with the DNMT1 DNA methyltransferase in mouse and human and regulates DNA methylation status of CpG island-associated promoters in trans. These results demonstrate, for the first time, that a single intergenic lncRNA controls the activity and methylation of genomically distal regulatory elements to modulate large-scale transcriptional programmes.

Original publication

DOI

10.7554/elife.04530

Type

Journal article

Journal

eLife

Publication Date

21/11/2014

Volume

3

Addresses

MRC Functional Genomics Unit, Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, United Kingdom.

Keywords

Neurons, Chromatin, Animals, Mice, Inbred C57BL, Humans, RNA, Messenger, Cell Differentiation, DNA Methylation, Transcription, Genetic, Epigenesis, Genetic, Conserved Sequence, Protein Binding, Cell Lineage, Promoter Regions, Genetic, Gene Knockdown Techniques, Genetic Loci, RNA, Long Noncoding