Allele-specific control of rodent and human lncRNA KMT2E-AS1 promotes hypoxic endothelial pathology in pulmonary hypertension-Reference-Cited by-同舟云学术

Allele-specific control of rodent and human lncRNA KMT2E-AS1 promotes hypoxic endothelial pathology in pulmonary hypertension

Published:2024-01-10 Issue:729 Volume:16 Page:
ISSN:1946-6234
Container-title:Science Translational Medicine
language:en
Short-container-title:Sci. Transl. Med.

Author:

Tai Yi-Yin¹²³⁴^ORCID,Yu Qiujun⁵^ORCID,Tang Ying¹²³⁴,Sun Wei¹²³⁴^ORCID,Kelly Neil J.¹²³⁴⁶^ORCID,Okawa Satoshi²³⁴⁷⁸,Zhao Jingsi¹²³⁴,Schwantes-An Tae-Hwi⁹¹⁰^ORCID,Lacoux Caroline¹¹^ORCID,Torrino Stephanie¹¹^ORCID,Al Aaraj Yassmin¹²³⁴^ORCID,El Khoury Wadih¹²³⁴^ORCID,Negi Vinny¹²⁴,Liu Mingjun²³⁴,Corey Catherine G.²⁴¹²¹³,Belmonte Frances²³⁴,Vargas Sara O.¹⁴,Schwartz Brian¹⁵^ORCID,Bhat Bal¹⁶,Chau B. Nelson¹⁷,Karnes Jason H.¹⁸^ORCID,Satoh Taijyu¹²³⁴¹⁹^ORCID,Barndt Robert J.¹²³⁴^ORCID,Wu Haodi¹²³⁴^ORCID,Parikh Victoria N.²⁰,Wang Jianrong²¹^ORCID,Zhang Yingze²⁴²²^ORCID,McNamara Dennis³⁴^ORCID,Li Gang²³⁴²³^ORCID,Speyer Gil²⁴^ORCID,Wang Bing⁴^ORCID,Shiva Sruti²⁴¹²²⁵^ORCID,Kaufman Brett²³⁴^ORCID,Kim Seungchan²⁶^ORCID,Gomez Delphine²³⁴^ORCID,Mari Bernard¹⁰^ORCID,Cho Michael H.²⁷^ORCID,Boueiz Adel²⁷^ORCID,Pauciulo Michael W.^ORCID,Southgate Laura²⁸²⁹^ORCID,Trembath Richard C.²⁸^ORCID,Sitbon Olivier³⁰^ORCID,Humbert Marc³⁰^ORCID,Graf Stefan³¹³²³³^ORCID,Morrell Nicholas W.³¹³⁴^ORCID,Rhodes Christopher J.³⁵^ORCID,Wilkins Martin R.³⁵^ORCID,Nouraie Mehdi¹²⁴²²^ORCID,Nichols William C.³⁶,Desai Ankit A.⁹,Bertero Thomas¹¹^ORCID,Chan Stephen Y.¹²³⁴^ORCID

Affiliation:

1. Center for Pulmonary Vascular Biology and Medicine, University of Pittsburgh School of Medicine and University of Pittsburgh Medical Center, Pittsburgh, PA 15213, USA.

2. Pittsburgh Heart, Lung, and Blood Vascular Medicine Institute, University of Pittsburgh School of Medicine and University of Pittsburgh Medical Center, Pittsburgh, PA 15213, USA.

3. Division of Cardiology, University of Pittsburgh School of Medicine and University of Pittsburgh Medical Center, Pittsburgh, PA 15213, USA.

4. Department of Medicine, University of Pittsburgh School of Medicine and University of Pittsburgh Medical Center, Pittsburgh, PA 15213, USA.

5. Cardiovascular Division, Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.

6. Pittsburgh VA Medical Center, Pittsburgh, PA 15240, USA.

7. Department of Computational and Systems Biology, University of Pittsburgh School of Medicine and University of Pittsburgh Medical Center, Pittsburgh, PA 15213, USA.

8. McGowan Institute for Regenerative Medicine, University of Pittsburgh School of Medicine and University of Pittsburgh Medical Center, Pittsburgh, PA 15219, USA.

9. Division of Cardiology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA.

10. Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN 46202, USA.

11. Université Côte d’Azur, CNRS, IPMC, IHU RespiERA, Sophia-Antipolis, 06903, France.

12. Center for Metabolism and Mitochondrial Medicine, University of Pittsburgh School of Medicine and University of Pittsburgh Medical Center, Pittsburgh, PA 15213, USA.

13. Department of Pediatrics, University of Pittsburgh Medical Center Children’s Hospital, Pittsburgh, PA 15224, USA.

14. Department of Pathology, Boston Children’s Hospital, Boston, MA 02115, USA.

15. Camp4 Therapeutics, Cambridge, MA 02139, USA.

16. Translate Bio, Lexington, MA 02421, USA.

17. Orna Therapeutics, Cambridge, MA 02139, USA.

18. Division of Pharmacogenomics, College of Pharmacy, University of Arizona College of Medicine, Tucson, AZ 85721, USA.

19. Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, Sendai, 980–8575, Japan.

20. Stanford Center for Inherited Cardiovascular Disease, Stanford University School of Medicine, Stanford, CA 94305, USA.

21. Department of Computational Mathematics, Science, and Engineering, Michigan State University, East Lansing, MI 48824, USA.

22. Division of Pulmonary, Allergy, and Critical Care Medicine, University of Pittsburgh School of Medicine and University of Pittsburgh Medical Center, Pittsburgh, PA 15213, USA.

23. Aging Institute, University of Pittsburgh, Pittsburgh, PA 15219, USA.

24. Research Computing, Arizona State University, Tempe, AZ 85281, USA.

25. Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, PA 15213, USA.

26. Center for Computational Systems Biology, Department of Electrical and Computer Engineering, Roy G. Perry College of Engineering, Prairie View A&M University, Prairie View, TX 77446, USA.

27. Channing Division of Network Medicine and Division of Pulmonary and Critical Care Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA 02115, USA.

28. Department of Medical and Molecular Genetics, Faculty of Life Sciences and Medicine, King’s College London, London, WC2R 2LS, UK.

29. Molecular and Clinical Sciences Research Institute, St George’s University of London, London, SW17 0RE, UK.

30. Université Paris–Saclay, INSERM, Assistance Publique Hôpitaux de Paris, Service de Pneumologie et Soins Intensifs Respiratoires, Hôpital Bicêtre, Le Kremlin Bicêtre, 94270, France.

31. Department of Medicine, University of Cambridge, Cambridge, CB2 1TN, UK.

32. NIHR BioResource for Translational Research, Cambridge Biomedical Campus, Cambridge, CB2 0QQ, UK.

33. Department of Haematology, University of Cambridge, NHS Blood and Transplant, Long Road, Cambridge, CB2 2PT, UK.

34. Centessa Pharmaceuticals, Altrincham, Cheshire, WA14 2DT, UK.

35. National Heart and Lung Institute, Imperial College London, London, SW3 6LY, UK.

36. Cincinnati Children’s Hospital Medical Center and the University of Cincinnati College of Medicine, Cincinnati, OH 45229, USA.

Abstract

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.

Publisher

American Association for the Advancement of Science (AAAS)

Subject

General Medicine

Link

https://www.science.org/doi/pdf/10.1126/scitranslmed.add2029

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