Recent studies have uncovered thousands of long non-coding RNAs (lncRNAs) in human pancreatic β cells. β cell lncRNAs are often cell type specific and exhibit dynamic regulation during differentiation or upon changing glucose concentrations. Although these features hint at a role of lncRNAs in β cell gene regulation and diabetes, the function of β cell lncRNAs remains largely unknown.
In this study, researchers from the Imperial College London investigated the function of β cell-specific lncRNAs and transcription factors using transcript knockdowns and co-expression network analysis. This revealed lncRNAs that function in concert with transcription factors to regulate β cell-specific transcriptional networks. They further demonstrate that the lncRNA PLUTO affects local 3D chromatin structure and transcription of PDX1, encoding a key β cell transcription factor, and that both PLUTO and PDX1 are downregulated in islets from donors with type 2 diabetes or impaired glucose tolerance. These results implicate lncRNAs in the regulation of β cell-specific transcription factor networks.
Islet-Specific Coding and Noncoding RNAs Form Shared Co-expression Modules
(A) Topological overlap matrix representing co-expression modules that were co-regulated across 64 human islet samples. Modules that were enriched in lncRNAs are marked with squares (hypergeometric test, p < 10−2).
(B–D) Co-expression modules that showed enrichment in islet lncRNAs (B), islet enhancer cluster (EC)-associated genes (C), or a set of 94 islet-enriched TF genes (D). Five modules (M3, M7, M12, M18, and M20, marked in blue) out of seven modules that were enriched in lncRNAs were also enriched in ECs and TFs.
(E) Module M3 was enriched in typical islet-specific biological process annotations. Right: examples of islet TFs and lncRNAs in module M3.
(F) Correlation of the indicated lncRNAs and β cell-specific TF mRNAs across 64 islet samples. GAPDH is shown as a non-β cell reference. Pearson’s correlation values are displayed in the top left corner. The axes show expression values normalized across 64 islet samples.
(G) Network diagram illustrating that TFs and lncRNAs often co-regulate the same genes, many of which are associated with enhancer clusters.