| Summary: | <p>Recently, long non-coding RNAs (lncRNAs) emerged as important regulators of many cellular functions. Many nuclear lncRNAs regulate the expression of geomically proximal or overlapping protein coding genes. Less clear is whether intergenic lncRNAs can regulate transcription by modulating chromatin at genomically distant loci in an RNA-dependent manner. This thesis investigated molecular functions of <em>Dali</em>, an intergenic central nervous system expressed lncRNA conserved in therian mammals. <em>Dali</em> is transcribed from a locus 50 kb downstream of the Pou3f3 transcription factor gene and performs both genomically local and distal RNA-dependent roles. Its depletion disrupts the differentiation of neuroblastoma cells. Locally, <em>Dali</em> regulates transcription of the <em>Pou3f3</em> locus. Distally, it preferentially binds near to and regulates active promoters across the genome, including by physically associating with the POU3F3 transcription factor. <em>Dali</em> also interacts with the DNMT1 DNA methyltransferase in mouse and human and regulates CpG island-associated promoters by modulating their DNA methylation levels in trans. This work is the first to demonstrate that a lncRNA can regulate the DNA methylation of CpG island-associated promoters <em>in trans</em> and one of the first large scale studies to identify direct transcriptional targets of a lncRNA genome-wide. It also provides a more detailed molecular dissection of the extended <em>Pou3f3</em> locus and a framework for the prioritisation and comprehensive functional characterisation of nuclear lncRNAs.</p>
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