The long noncoding RNA CHROME regulates cholesterol homeostasis in primates

Elizabeth J. Hennessy, Coen van Solingen, Kaitlyn R. Scacalossi, Mireille Ouimet, Milessa S. Afonso, Jurrien Prins, Graeme J. Koelwyn, Monika Sharma, Bhama Ramkhelawon, Susan Carpenter, Albert Busch, Ekaterina Chernogubova, Ljubica Perisic Matic, Ulf Hedin, Lars Maegdefessel, Brian E. Caffrey, Maryem A. Hussein, Emiliano P. Ricci, Ryan E. Temel, Michael J. GarabedianJeffrey S. Berger, Kasey C. Vickers, Matthew Kanke, Praveen Sethupathy, Daniel Teupser, Lesca M. Holdt, Kathryn J. Moore

Research output: Contribution to journalArticlepeer-review

102 Scopus citations

Abstract

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.

Original languageEnglish
Pages (from-to)98-110
Number of pages13
JournalNature Metabolism
Volume1
Issue number1
DOIs
StatePublished - Jan 1 2019

Bibliographical note

Publisher Copyright:
© 2018, The Author(s), under exclusive licence to Springer Nature Limited.

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism
  • Physiology (medical)
  • Cell Biology

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