Historically, it was thought that the primary function of RNA in a cell was to code for proteins and proteins, in turn, were solely responsible for gene regulation. These notions have been challenged in recent decades by the discovery that the eukaryotic genome codes for a vast number of functional non-protein-coding RNAs (ncRNAs), such as long noncoding RNAs (lncRNAs), defined as transcripts longer than 200 nucleotides that lack protein-coding potential. Thousands of lncRNAs have since been identified in numerous cell types and different model organisms; however, with a few important exceptions, their function is mostly unknown. The lncRNAs that have been carefully analyzed regulate processes as varied as imprinting, dosage compensation, pluripotency and apoptosis. Intriguingly, lncRNAs can regulate the expression of genes in cis or in trans by direct binding to transcription factors or by recruiting chromatin-modifying complexes. Additionally, several lncRNAs have been shown to function post-transcriptionally by altering splicing or mRNA stability. The establishment of these complex lncRNA regulatory mechanisms invokes a need to reassess biological questions in the context of a role for lncRNAs. While evidence suggests a role for lncRNAs in the disease- relevant pancreas, functional characterization of pancreatic lncRNAs is lacking. To understand how lncRNAs promote proper pancreas development and function, we have conducted comprehensive transcriptome analysis of embryonic mouse pancreas and adult mouse islets. Our preliminary results revealed several novel pancreatic lncRNA that lie in close proximity to pancreas-related genes and are both syntentically and sequentially conserved in humans. Additionally, these novel lncRNAs are expressed in a temporal manner suggestive of function. This study will seek to characterize pancreatic lncRNAs and determine their mechanism of function. With these analyses, we can uncover a novel layer of gene regulation and greatly enhance our understanding of the complex regulatory mechanisms that promote pancreas development and maintain a functional adult pancreas.
Our ability to understand and treat diabetes is limited by the gaps in our knowledge of the regulatory mechanisms that orchestrate pancreas development and maintain a functional adult pancreas. Long noncoding RNAs (lncRNAs) have been implicated in many essential regulatory pathways and are misregulated in diseased states. This study will seek to characterize pancreatic lncRNAs and uncover novel regulatory mechanisms that promote pancreas specification and function.
|Churchill, Angela J; Gutiérrez, Giselle Dominguez; Singer, Ruth A et al. (2017) Genetic evidence that Nkx2.2 acts primarily downstream of Neurog3 in pancreatic endocrine lineage development. Elife 6:|