Section of Genetics and Genomics, Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK.
Centre for Genomic Regulation, Barcelona Institute of Science and Technology, Barcelona, Spain.
Nat Cell Biol. 2022 Oct;24(10):1528-1540. doi: 10.1038/s41556-022-00996-8. Epub 2022 Oct 6.
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 β 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.
长链非编码 RNA（lncRNA）的生物学功能尚未完全阐明。编码同源结构域转录因子的 HNF1A 同源盒 A（HNF1A）单倍不足突变会导致糖尿病。在这里，我们研究了 HASTER，这是编码 HNF1A 反义 lncRNA 的启动子。使用小鼠和人类模型，我们表明 HASTER 通过正反馈和负反馈环维持细胞特异性生理 HNF1A 浓度。因此，来自 Haster 突变小鼠的胰岛β细胞表现出 HNF1A 沉默或过表达的不均匀性，导致高血糖。HASTER 依赖性负反馈对于防止 HNF1A 与不适当的基因组区域结合至关重要。我们证明，HASTER 启动子 DNA 而不是 lncRNA，在顺式中调节 HNF1A 启动子增强子相互作用，从而调节 HNF1A 转录。我们的研究揭示了一种不同于经典增强子或沉默子的顺式调节元件，它稳定了靶基因的转录，并确保了细胞特异性转录因子程序的保真度。它们还表明，破坏哺乳动物 lncRNA 启动子可导致糖尿病。
