| First Author | Beucher A | Year | 2022 |
| Journal | Nat Cell Biol | Volume | 24 |
| Issue | 10 | Pages | 1528-1540 |
| PubMed ID | 36202974 | Mgi Jnum | J:332319 |
| Mgi Id | MGI:7414465 | Doi | 10.1038/s41556-022-00996-8 |
| Citation | Beucher A, et al. (2022) The HASTER lncRNA promoter is a cis-acting transcriptional stabilizer of HNF1A. Nat Cell Biol 24(10):1528-1540 |
| abstractText | The biological purpose of long non-coding RNAs (lncRNAs) is poorly understood. Haploinsufficient mutations in HNF1A homeobox A (HNF1A), encoding a homeodomain transcription factor, cause diabetes mellitus. Here, we examine HASTER, the promoter of an lncRNA antisense to HNF1A. Using mouse and human models, we show that HASTER maintains cell-specific physiological HNF1A concentrations through positive and negative feedback loops. Pancreatic beta cells from Haster mutant mice consequently showed variegated HNF1A silencing or overexpression, resulting in hyperglycaemia. HASTER-dependent negative feedback was essential to prevent HNF1A binding to inappropriate genomic regions. We demonstrate that the HASTER promoter DNA, rather than the lncRNA, modulates HNF1A promoter-enhancer interactions in cis and thereby regulates HNF1A transcription. Our studies expose a cis-regulatory element that is unlike classic enhancers or silencers, it stabilizes the transcription of its target gene and ensures the fidelity of a cell-specific transcription factor program. They also show that disruption of a mammalian lncRNA promoter can cause diabetes mellitus. |
