The HASTER lncRNA promoter is a cis-acting transcriptional stabilizer of HNF1A
© 2022. The Author(s)..
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.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2022 |
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| Erschienen: |
2022 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:24 |
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| Enthalten in: |
Nature cell biology - 24(2022), 10 vom: 28. Okt., Seite 1528-1540 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Beucher, Anthony [VerfasserIn] |
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| Links: |
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| Themen: |
HNF1A protein, human |
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| Anmerkungen: |
Date Completed 01.11.2022 Date Revised 14.02.2024 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1038/s41556-022-00996-8 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM347183360 |
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| 245 | 1 | 4 | |a The HASTER lncRNA promoter is a cis-acting transcriptional stabilizer of HNF1A |
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| 520 | |a © 2022. The Author(s). | ||
| 520 | |a 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 | ||
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| 650 | 7 | |a Hepatocyte Nuclear Factor 1-alpha |2 NLM | |
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| 700 | 1 | |a Miguel-Escalada, Irene |e verfasserin |4 aut | |
| 700 | 1 | |a Balboa, Diego |e verfasserin |4 aut | |
| 700 | 1 | |a De Vas, Matías G |e verfasserin |4 aut | |
| 700 | 1 | |a Maestro, Miguel Angel |e verfasserin |4 aut | |
| 700 | 1 | |a Garcia-Hurtado, Javier |e verfasserin |4 aut | |
| 700 | 1 | |a Bernal, Aina |e verfasserin |4 aut | |
| 700 | 1 | |a Gonzalez-Franco, Roser |e verfasserin |4 aut | |
| 700 | 1 | |a Vargiu, Pierfrancesco |e verfasserin |4 aut | |
| 700 | 1 | |a Heyn, Holger |e verfasserin |4 aut | |
| 700 | 1 | |a Ravassard, Philippe |e verfasserin |4 aut | |
| 700 | 1 | |a Ortega, Sagrario |e verfasserin |4 aut | |
| 700 | 1 | |a Ferrer, Jorge |e verfasserin |4 aut | |
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