Allele-specific control of rodent and human lncRNA KMT2E-AS1 promotes hypoxic endothelial pathology in pulmonary hypertension
Hypoxic reprogramming of vasculature relies on genetic, epigenetic, and metabolic circuitry, but the control points are unknown. In pulmonary arterial hypertension (PAH), a disease driven by hypoxia inducible factor (HIF)-dependent vascular dysfunction, HIF-2α promoted expression of neighboring genes, long noncoding RNA (lncRNA) histone lysine N-methyltransferase 2E-antisense 1 (KMT2E-AS1) and histone lysine N-methyltransferase 2E (KMT2E). KMT2E-AS1 stabilized KMT2E protein to increase epigenetic histone 3 lysine 4 trimethylation (H3K4me3), driving HIF-2α-dependent metabolic and pathogenic endothelial activity. This lncRNA axis also increased HIF-2α expression across epigenetic, transcriptional, and posttranscriptional contexts, thus promoting a positive feedback loop to further augment HIF-2α activity. We identified a genetic association between rs73184087, a single-nucleotide variant (SNV) within a KMT2E intron, and disease risk in PAH discovery and replication patient cohorts and in a global meta-analysis. This SNV displayed allele (G)-specific association with HIF-2α, engaged in long-range chromatin interactions, and induced the lncRNA-KMT2E tandem in hypoxic (G/G) cells. In vivo, KMT2E-AS1 deficiency protected against PAH in mice, as did pharmacologic inhibition of histone methylation in rats. Conversely, forced lncRNA expression promoted more severe PH. Thus, the KMT2E-AS1/KMT2E pair orchestrates across convergent multi-ome landscapes to mediate HIF-2α pathobiology and represents a key clinical target in pulmonary hypertension.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:16 |
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| Enthalten in: |
Science translational medicine - 16(2024), 729 vom: 10. Jan., Seite eadd2029 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Tai, Yi-Yin [VerfasserIn] |
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| Links: |
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| Themen: |
Basic Helix-Loop-Helix Transcription Factors |
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| Anmerkungen: |
Date Completed 12.01.2024 Date Revised 22.03.2024 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1126/scitranslmed.add2029 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM366891618 |
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| 245 | 1 | 0 | |a Allele-specific control of rodent and human lncRNA KMT2E-AS1 promotes hypoxic endothelial pathology in pulmonary hypertension |
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| 520 | |a Hypoxic reprogramming of vasculature relies on genetic, epigenetic, and metabolic circuitry, but the control points are unknown. In pulmonary arterial hypertension (PAH), a disease driven by hypoxia inducible factor (HIF)-dependent vascular dysfunction, HIF-2α promoted expression of neighboring genes, long noncoding RNA (lncRNA) histone lysine N-methyltransferase 2E-antisense 1 (KMT2E-AS1) and histone lysine N-methyltransferase 2E (KMT2E). KMT2E-AS1 stabilized KMT2E protein to increase epigenetic histone 3 lysine 4 trimethylation (H3K4me3), driving HIF-2α-dependent metabolic and pathogenic endothelial activity. This lncRNA axis also increased HIF-2α expression across epigenetic, transcriptional, and posttranscriptional contexts, thus promoting a positive feedback loop to further augment HIF-2α activity. We identified a genetic association between rs73184087, a single-nucleotide variant (SNV) within a KMT2E intron, and disease risk in PAH discovery and replication patient cohorts and in a global meta-analysis. This SNV displayed allele (G)-specific association with HIF-2α, engaged in long-range chromatin interactions, and induced the lncRNA-KMT2E tandem in hypoxic (G/G) cells. In vivo, KMT2E-AS1 deficiency protected against PAH in mice, as did pharmacologic inhibition of histone methylation in rats. Conversely, forced lncRNA expression promoted more severe PH. Thus, the KMT2E-AS1/KMT2E pair orchestrates across convergent multi-ome landscapes to mediate HIF-2α pathobiology and represents a key clinical target in pulmonary hypertension | ||
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| 700 | 1 | |a Tang, Ying |e verfasserin |4 aut | |
| 700 | 1 | |a Sun, Wei |e verfasserin |4 aut | |
| 700 | 1 | |a Kelly, Neil J |e verfasserin |4 aut | |
| 700 | 1 | |a Okawa, Satoshi |e verfasserin |4 aut | |
| 700 | 1 | |a Zhao, Jingsi |e verfasserin |4 aut | |
| 700 | 1 | |a Schwantes-An, Tae-Hwi |e verfasserin |4 aut | |
| 700 | 1 | |a Lacoux, Caroline |e verfasserin |4 aut | |
| 700 | 1 | |a Torrino, Stephanie |e verfasserin |4 aut | |
| 700 | 1 | |a Al Aaraj, Yassmin |e verfasserin |4 aut | |
| 700 | 1 | |a El Khoury, Wadih |e verfasserin |4 aut | |
| 700 | 1 | |a Negi, Vinny |e verfasserin |4 aut | |
| 700 | 1 | |a Liu, Mingjun |e verfasserin |4 aut | |
| 700 | 1 | |a Corey, Catherine G |e verfasserin |4 aut | |
| 700 | 1 | |a Belmonte, Frances |e verfasserin |4 aut | |
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| 700 | 1 | |a Satoh, Taijyu |e verfasserin |4 aut | |
| 700 | 1 | |a Barndt, Robert J |e verfasserin |4 aut | |
| 700 | 1 | |a Wu, Haodi |e verfasserin |4 aut | |
| 700 | 1 | |a Parikh, Victoria N |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Jianrong |e verfasserin |4 aut | |
| 700 | 1 | |a Zhang, Yingze |e verfasserin |4 aut | |
| 700 | 1 | |a McNamara, Dennis |e verfasserin |4 aut | |
| 700 | 1 | |a Li, Gang |e verfasserin |4 aut | |
| 700 | 1 | |a Speyer, Gil |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Bing |e verfasserin |4 aut | |
| 700 | 1 | |a Shiva, Sruti |e verfasserin |4 aut | |
| 700 | 1 | |a Kaufman, Brett |e verfasserin |4 aut | |
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| 700 | 1 | |a Mari, Bernard |e verfasserin |4 aut | |
| 700 | 1 | |a Cho, Michael H |e verfasserin |4 aut | |
| 700 | 1 | |a Boueiz, Adel |e verfasserin |4 aut | |
| 700 | 1 | |a Pauciulo, Michael W |e verfasserin |4 aut | |
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