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Current opinion in cardiology
05 01, 2023;38 (3): 179-192.

Long noncoding RNAs in cardiovascular disease.

Alexander Kohlmaier, Lesca M Holdt, Daniel Teupser
Author Information
  1. Alexander Kohlmaier: Institute of Laboratory Medicine, University Hospital, LMU Munich, Munich, Germany.
PMID: 36930221 DOI: 10.1097/HCO.0000000000001041

Abstract

PURPOSE OF REVIEW: Here, we review recent findings on the role of long noncoding RNAs (lncRNAs) in cardiovascular disease (CVD). In addition, we highlight some of the latest findings in lncRNA biology, providing an outlook for future avenues of lncRNA research in CVD.
RECENT FINDINGS: Recent publications provide translational evidence from patient studies and animal models for the role of specific lncRNAs in CVD. The molecular effector mechanisms of these lncRNAs are diverse. Overall, cell-type selective modulation of gene expression is the largest common denominator. New methods, such as single-cell profiling and CRISPR/Cas9-screening, reveal additional novel mechanistic principles: For example, many lncRNAs establish RNA-based spatial compartments that concentrate effector proteins. Also, RNA modifications and splicing features can be determinants of lncRNA function.
SUMMARY: lncRNA research is passing the stage of enumerating lncRNAs or recording simplified on-off expression switches. Mechanistic analyses are starting to reveal overarching principles of how lncRNAs can function. Exploring these principles with decisive genetic testing in vivo remains the ultimate test to discern how lncRNA loci, by RNA motifs or DNA elements, affect CVD pathophysiology.

References

  1. Vaduganathan M, Mensah GA, Turco JV, et al. The global burden of cardiovascular diseases and risk: a compass for future health. J Am Coll Cardiol 2022; 80:2361–2371.
  2. Mattick JS, Amaral PP, Carninci P, et al. Long noncoding RNAs: definitions, functions, challenges and recommendations. Nat Rev Mol Cell Biol 2023; doi: 10.1038/s41580-022-00566-8. [Online ahead of print]. [DOI: 10.1038/s41580-022-00566-8.]
  3. Andergassen D, Rinn JL. From genotype to phenotype: genetics of mammalian long noncoding RNAs in vivo . Nat Rev Genet 2022; 23:229–243.
  4. Holdt LM, Kohlmaier A, Teupser D. Erdmann J, Moretti A. Long noncoding RNAs in cardiovascular disease. Genetic causes of cardiac disease. Cham: Springer International Publishing; 2019. 199–288.
  5. Dong K, Shen J, He X, et al. CARMN is an evolutionarily conserved smooth muscle cell-specific LncRNA that maintains contractile phenotype by binding myocardin. Circulation 2021; 144:1856–1875.
  6. Ni H, Haemmig S, Deng Y, et al. A smooth muscle cell-enriched long noncoding RNA regulates cell plasticity and atherosclerosis by interacting with serum response factor. Arterioscler Thromb Vasc Biol 2021; 41:2399–2416.
  7. Vacante F, Rodor J, Lalwani MK, et al. CARMN loss regulates smooth muscle cells and accelerates atherosclerosis in mice. Circ Res 2021; 128:1258–1275.
  8. Gao R, Wang L, Bei Y, et al. Long noncoding RNA cardiac physiological hypertrophy-associated regulator induces cardiac physiological hypertrophy and promotes functional recovery after myocardial ischemia-reperfusion injury. Circulation 2021; 144:303–317.
  9. Dong XH, Lu ZF, Kang CM, et al. The long noncoding RNA RP11-728F11.4 promotes atherosclerosis. Arterioscler Thromb Vasc Biol 2021; 41:1191–1204.
  10. Hazra R, Brine L, Garcia L, et al. Platr4 is an early embryonic lncRNA that exerts its function downstream on cardiogenic mesodermal lineage commitment. Dev Cell 2022; 57:2450–2468. e7.
  11. Li H, Trager LE, Liu X, et al. lncExACT1 and DCHS2 regulate physiological and pathological cardiac growth. Circulation 2022; 145:1218–1233.
  12. Wang J, Liu S, Heallen T, Martin JF. The Hippo pathway in the heart: pivotal roles in development, disease, and regeneration. Nat Rev Cardiol 2018; 15:672–684.
  13. Zhao Y, Riching AS, Knight WE, et al. Cardiomyocyte-specific long noncoding RNA regulates alternative splicing of the Triadin gene in the heart. Circulation 2022; 146:699–714.
  14. Fan J, Li H, Xie R, et al. LncRNA ZNF593-AS alleviates contractile dysfunction in dilated cardiomyopathy. Circ Res 2021; 128:1708–1723.
  15. Ren X, Zhu H, Deng K, et al. Long noncoding RNA TPRG1-AS1 suppresses migration of vascular smooth muscle cells and attenuates atherogenesis via interacting with MYH9 protein. Arterioscler Thromb Vasc Biol 2022; 42:1378–1397.
  16. Xiao H, Zhang M, Wu H, et al. CIRKIL exacerbates cardiac ischemia/reperfusion injury by interacting with Ku70. Circ Res 2022; 130:e3–e17.
  17. Park KS, Rahat B, Lee HC, et al. Cardiac pathologies in mouse loss of imprinting models are due to misexpression of H19 long noncoding RNA. Elife 2021; 10:e67250.
  18. Lu D, Chatterjee S, Xiao K, et al. A circular RNA derived from the insulin receptor locus protects against doxorubicin-induced cardiotoxicity. Eur Heart J 2022.
  19. Sato M, Kadomatsu T, Miyata K, et al. The lncRNA Caren antagonizes heart failure by inactivating DNA damage response and activating mitochondrial biogenesis. Nat Commun 2021; 12:2529.
  20. Fasolo F, Jin H, Winski G, et al. Long noncoding RNA MIAT controls advanced atherosclerotic lesion formation and plaque destabilization. Circulation 2021; 144:1567–1583.
  21. Peng KL, Vasudevan HN, Lockney DT, et al. Miat and interacting protein Metadherin maintain a stem-like niche to promote medulloblastoma tumorigenesis and treatment resistance. Proc Natl Acad Sci U S A 2022; 119:e2203738119.
  22. Zhuang A, Calkin AC, Lau S, et al. Loss of the long noncoding RNA OIP5-AS1 exacerbates heart failure in a sex-specific manner. iScience 2021; 24:102537.
  23. Liu J, Liu S, Han L, et al. LncRNA HBL1 is required for genome-wide PRC2 occupancy and function in cardiogenesis from human pluripotent stem cells. Development 2021; 148:dev199628.
  24. Zhao Y, Ling S, Li J, et al. 3’ untranslated region of Ckip-1 inhibits cardiac hypertrophy independently of its cognate protein. Eur Heart J 2021; 42:3786–3799.
  25. Sehgal P, Mathew S, Sivadas A, et al. LncRNA VEAL2 regulates PRKCB2 to modulate endothelial permeability in diabetic retinopathy. EMBO J 2021; 40:e107134.
  26. de Goede OM, Nachun DC, Ferraro NM, et al. Population-scale tissue transcriptomics maps long noncoding RNAs to complex disease. Cell 2021; 184:2633–2648. e19.
  27. Turner AW, Hu SS, Mosquera JV, et al. Single-nucleus chromatin accessibility profiling highlights regulatory mechanisms of coronary artery disease risk. Nat Genet 2022; 54:804–816.
  28. Zhang K, Hocker JD, Miller M, et al. A single-cell atlas of chromatin accessibility in the human genome. Cell 2021; 184:5985–6001. e19.
  29. Ameen M, Sundaram L, Shen M, et al. Integrative single-cell analysis of cardiogenesis identifies developmental trajectories and noncoding mutations in congenital heart disease. Cell 2022; 185:4937–4953. e23.
  30. Findley AS, Monziani A, Richards AL, et al. Functional dynamic genetic effects on gene regulation are specific to particular cell types and environmental conditions. Elife 2021. 10.
  31. Yazar S, Alquicira-Hernandez J, Wing K, et al. Single-cell eQTL mapping identifies cell type-specific genetic control of autoimmune disease. Science 2022; 376:eabf3041.
  32. Nasser J, Bergman DT, Fulco CP, et al. Genome-wide enhancer maps link risk variants to disease genes. Nature 2021; 593:238–243.
  33. Lin X, Liu Y, Liu S, et al. Nested epistasis enhancer networks for robust genome regulation. Science 2022; 377:1077–1085.
  34. Johnsson P, Ziegenhain C, Hartmanis L, et al. Transcriptional kinetics and molecular functions of long noncoding RNAs. Nat Genet 2022; 54:306–317.
  35. Dukler N, Mughal MR, Ramani R, et al. Extreme purifying selection against point mutations in the human genome. Nat Commun 2022; 13:4312.
  36. Cao T, O’Reilly ME, Selvaggi C, et al. Cis-regulated expression of nonconserved lincRNAs associates with cardiometabolic related traits. J Hum Genet 2022; 67:307–310.
  37. Ross CJ, Ulitsky I. Discovering functional motifs in long noncoding RNAs. Wiley Interdiscip Rev RNA 2022; 13:e1708.
  38. Ponting CP, Haerty W. Genome-wide analysis of human long noncoding RNAs: a provocative review. Annu Rev Genomics Hum Genet 2022; 23:153–172.
  39. Gebauer F, Schwarzl T, Valcarcel J, Hentze MW. RNA-binding proteins in human genetic disease. Nat Rev Genet 2021; 22:185–198.
  40. Wu D, Poddar A, Ninou E, et al. Dual genome-wide coding and lncRNA screens in neural induction of induced pluripotent stem cells. Cell Genom 2022; 2:
  41. Liu SJ, Horlbeck MA, Cho SW, et al. CRISPRi-based genome-scale identification of functional long noncoding RNA loci in human cells. Science 2017; 355:
  42. Creamer KM, Kolpa HJ, Lawrence JB. Nascent RNA scaffolds contribute to chromosome territory architecture and counter chromatin compaction. Mol Cell 2021; 81:3509–3525. e5.
  43. Quinodoz SA, Jachowicz JW, Bhat P, et al. RNA promotes the formation of spatial compartments in the nucleus. Cell 2021; 184:5775–5790. e30.
  44. Unfried JP, Ulitsky I. Substoichiometric action of long noncoding RNAs. Nat Cell Biol 2022; 24:608–615.
  45. Henninger JE, Oksuz O, Shrinivas K, et al. RNA-mediated feedback control of transcriptional condensates. Cell 2021; 184:207–225. e24.
  46. Engreitz JM, Haines JE, Perez EM, et al. Local regulation of gene expression by lncRNA promoters, transcription and splicing. Nature 2016; 539:452–455.
  47. Dumbovic G, Braunschweig U, Langner HK, et al. Nuclear compartmentalization of TERT mRNA and TUG1 lncRNA is driven by intron retention. Nat Commun 2021; 12:3308.
  48. Lee LA, Broadwell LJ, Buvoli M, Leinwand LA. Nonproductive splicing prevents expression of MYH7b protein in the mammalian heart. J Am Heart Assoc 2021; 10:e020965.
  49. Barbieri I, Kouzarides T. Role of RNA modifications in cancer. Nat Rev Cancer 2020; 20:303–322.
  50. Jones AN, Tikhaia E, Mourao A, Sattler M. Structural effects of m6A modification of the Xist A-repeat AUCG tetraloop and its recognition by YTHDC1. Nucleic Acids Res 2022; 50:2350–2362.
  51. Wang ZW, Pan JJ, Hu JF, et al. SRSF3-mediated regulation of N6-methyladenosine modification-related lncRNA ANRIL splicing promotes resistance of pancreatic cancer to gemcitabine. Cell Rep 2022; 39:110813.
  52. Patraquim P, Magny EG, Pueyo JI, et al. Translation and natural selection of micropeptides from long noncanonical RNAs. Nat Commun 2022; 13:6515.
  53. Chothani SP, Adami E, Widjaja AA, et al. A high-resolution map of human RNA translation. Mol Cell 2022; 82:2885–2899. e8.
  54. Yu J, Wang W, Yang J, et al. LncRNA PSR regulates vascular remodeling through encoding a novel protein arteridin. Circ Res 2022; 131:768–787.
  55. Guo JK, Guttman M. Regulatory noncoding RNAs: everything is possible, but what is important? Nat Methods 2022; 19:1156–1159.
  56. Hafner M, Katsantoni M, Köster T, et al. CLIP and complementary methods. Nat Rev Methods Primers 2021; 1:20.
  57. Rosenberg M, Blum R, Kesner B, et al. Motif-driven interactions between RNA and PRC2 are rheostats that regulate transcription elongation. Nat Struct Mol Biol 2021; 28:103–117.

MeSH Term

Animals
Humans
RNA, Long Noncoding
Cardiovascular Diseases

Chemicals

RNA, Long Noncoding
Review Journal Article Research Support, Non-U.S. Gov't
Article has an altmetric score of 3

Word Cloud

Created with Highcharts 10.0.0lncRNAslncRNACVDfindingsrolenoncodingRNAscardiovasculardiseaseresearcheffectorexpressionrevealRNAcanfunctionprinciplesPURPOSEOFREVIEW:reviewrecentlongadditionhighlightlatestbiologyprovidingoutlookfutureavenuesRECENTFINDINGS:RecentpublicationsprovidetranslationalevidencepatientstudiesanimalmodelsspecificmolecularmechanismsdiverseOverallcell-typeselectivemodulationgenelargestcommondenominatorNewmethodssingle-cellprofilingCRISPR/Cas9-screeningadditionalnovelmechanisticprinciples:examplemanyestablishRNA-basedspatialcompartmentsconcentrateproteinsAlsomodificationssplicingfeaturesdeterminantsSUMMARY:passingstageenumeratingrecordingsimplifiedon-offswitchesMechanisticanalysesstartingoverarchingExploringdecisivegenetictestingvivoremainsultimatetestdiscernlocimotifsDNAelementsaffectpathophysiologyLong

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