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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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.
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.
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Hennessy, E.J., van Solingen, C., Scacalossi, K.R. et al. The long noncoding RNA CHROME regulates cholesterol homeostasis in primates. Nat Metab 1, 98–110 (2019). https://doi.org/10.1038/s42255-018-0004-9
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