The human genome encodes thousands of long noncoding RNAs (lncRNAs), the majority of which are poorly conserved and uncharacterized. Here we identify a primate-specific lncRNA (CHROME), which is elevated in the plasma and atherosclerotic plaques of individuals with coronary artery disease, and regulates cellular and systemic cholesterol homeostasis. Expression of the lncRNA CHROME is influenced by dietary and cellular cholesterol through the sterol-activated liver X receptor transcription factors, which control genes that mediate responses to cholesterol overload. Using gain- and loss-of-function approaches, we show that CHROME promotes cholesterol efflux and high-density lipoprotein (HDL) biogenesis by curbing the actions of a set of functionally related microRNAs that repress genes in those pathways. CHROME knockdown in human hepatocytes and macrophages increases the levels of miR-27b, miR-33a, miR-33b and miR-128, thereby reducing the expression of their overlapping target gene networks and associated biological functions. In particular, cells that lack CHROME show reduced expression of ABCA1, which regulates cholesterol efflux and nascent HDL particle formation. Collectively, our findings identify CHROME as a central component of the noncoding RNA circuitry that controls cholesterol homeostasis in humans.

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Data availabilty

The Biobank of Karolinska Endarterectomies (BiKE) microarray dataset has been deposited in the Gene Expression Omnibus (GEO) and is available under accession GSE21545. HepG2 RNA-sequencing datasets have been deposited in GEO under accession GSE97469. Data that support the plots within this paper and other findings of this study are available from the corresponding author upon reasonable request.

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This work was supported by grants from the NIH (R01HL119047 (K.J.M.), R35HL135799 (K.J.M.), R01HL117226 (M.J.G.), T32HL098129 (E.J.H., C.v.S.), R01HL114978 (J.S.B.), R00HL088528 (R.E.T.), R01HL111932 (R.E.T.), R01HL128996 (K.C.V.), P01HL116263 (K.C.V.), R01DK105965 (P.S.)), the American Heart Association (14POST20180018 (C.v.S.), 13CRP14410042 (J.S.B.)), FINOVI (E.P.R.), the Swedish Society for Medical Research (L.P.M.) and the Heart and Lung Foundation (L.P.M.), the German Research Foundation CRC 1123 Project B1 (D.T. and L.M.H.), German Biobank Alliance BMBF 01EY1711C (German Ministry of Education and Research to D.T. and L.M.H.) and the Leducq Foundation CAD genomics (D.T. and L.M.H.). The BiKE study was supported by the Swedish Heart and Lung Foundation, the Swedish Research Council (K2009-65X-2233-01-3, K2013-65X-06816-30-4, 349-2007-8703), Uppdrag Besegra Stroke (P581/2011-123), the Strategic Cardiovascular Programs of Karolinska Institutet and Stockholm County Council, the Foundation for Strategic Research and the European Commission (CarTarDis, AtheroRemo, VIA, AtheroFlux projects). We thank E. A. Fisher (New York University) for helpful discussions, and S. Zhao and Q. Sheng (Vanderbilt University) for their efforts in sequencing-data analysis.

Author information

Author notes

  1. These authors contributed equally: E. J. Hennessy, C. v. Solingen.


  1. Department of Medicine, Leon H. Charney Division of Cardiology, New York University School of Medicine, New York, NY, USA

    • Elizabeth J. Hennessy
    • , Coen van Solingen
    • , Kaitlyn R. Scacalossi
    • , Mireille Ouimet
    • , Milessa S. Afonso
    • , Graeme J. Koelwyn
    • , Monika Sharma
    • , Bhama Ramkhelawon
    • , Jeffrey S. Berger
    •  & Kathryn J. Moore
  2. Department of Internal Medicine (Nephrology), Einthoven Laboratory for Vascular and Regenerative Medicine, Leiden University Medical Center, Leiden, the Netherlands

    • Jurrien Prins
  3. Department of Molecular, Cell and Developmental Biology, University of California, Santa Cruz, Santa Cruz, CA, USA

    • Susan Carpenter
  4. Department of Molecular Medicine and Surgery, Karolinska Institute, Stockholm, Sweden

    • Albert Busch
    • , Ekaterina Chernogubova
    • , Ljubica Perisic Matic
    • , Ulf Hedin
    •  & Lars Maegdefessel
  5. Department of Vascular and Endovascular Surgery, Klinikum Rechts der Isar, Technical University Munich, Munich, Germany

    • Albert Busch
    •  & Lars Maegdefessel
  6. Max Planck Institute for Molecular Genetics, Berlin, Germany

    • Brian E. Caffrey
  7. Department of Microbiology, New York University School of Medicine, New York, NY, USA

    • Maryem A. Hussein
    •  & Michael J. Garabedian
  8. INSERM U1111, Centre International de Recherche en Infectiologie, Ecole Normale Supérieure de Lyon, Université de Lyon, Lyon, France

    • Emiliano P. Ricci
  9. Saha Cardiovascular Research Center, University of Kentucky, Lexington, KY, USA

    • Ryan E. Temel
  10. Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA

    • Kasey C. Vickers
  11. Department of Biomedical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY, USA

    • Matthew Kanke
    •  & Praveen Sethupathy
  12. Institute of Laboratory Medicine, Ludwig-Maximilians-University Munich, Munich, Germany

    • Daniel Teupser
    •  & Lesca M. Holdt


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E.J.H., C.v.S. and K.J.M. designed the study, guided the interpretation of the results and prepared the manuscript, with input from all authors. E.J.H. and C.v.S. performed experiments and data analyses. K.R.S., M.O., M.S.A., J.P., G.J.K., M.S., B.R., K.C.V., M.K. and P.S. contributed to experiments and data analyses. S.C. created and analyzed stable cell lines. A.B. and M.O. performed in situ hybridization of human plaques. E.C., L.P.M., U.H. and L.M. processed and analyzed BiKE datasets. B.E.C. performed RNAcofold and RNAhybrid analyses. E.P.R. performed polysome fractionation experiments. R.E.T. supervised nonhuman primate studies. M.A.H. and M.J.G. performed chromatin immunoprecipitation experiments. J.S.B. provided human plasma samples and assisted in data interpretation. D.T. and L.M.H. performed human liver RNA and lipoprotein analyses.

Competing interests

K.J.M. and New York University hold a patent (US 9241950, status: issued 26 January 2016) on the use of miR-33 inhibitors to treat inflammation. All other authors have no competing interests.

Corresponding author

Correspondence to Kathryn J. Moore.

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