The long noncoding RNA CHROME regulates cholesterol homeostasis in primate

Research output: Contribution to journalResearch articleContributedpeer-review

Contributors

  • Elizabeth J Hennessy - , New York University (Author)
  • Coen van Solingen - , New York University (Author)
  • Kaitlyn R Scacalossi - , New York University (Author)
  • Mireille Ouimet - , New York University (Author)
  • Milessa S Afonso - , New York University (Author)
  • Jurrien Prins - , Leiden University (Author)
  • Graeme J Koelwyn - , New York University (Author)
  • Monika Sharma - , New York University (Author)
  • Bhama Ramkhelawon - , New York University (Author)
  • Susan Carpenter - , Dominican University of California (Author)
  • Albert Busch - , Karolinska Institutet, Klinikum Rechts der Isar (MRI TUM), Technical University of Munich (Author)
  • Ekaterina Chernogubova - , Karolinska Institutet (Author)
  • Ljubica Perisic Matic - , Karolinska Institutet (Author)
  • Ulf Hedin - , Karolinska Institutet (Author)
  • Lars Maegdefessel - , Karolinska Institutet (Author)
  • Brian E Caffrey - , Max Planck Institute for Molecular Genetics (Author)
  • Maryem A Hussein - , New York University (Author)
  • Emiliano P Ricci - , Centre International de Recherche en Infectiologie (Author)
  • Ryan E Temel - , University of Kentucky (Author)
  • Michael J Garabedian - , New York University (Author)
  • Jeffrey S Berger - , New York University (Author)
  • Kasey C Vickers - , Vanderbilt University (Author)
  • Matthew Kanke - , Cornell University (Author)
  • Praveen Sethupathy - , Cornell University (Author)
  • Daniel Teupser - , Ludwig Maximilian University of Munich (Author)
  • Lesca M Holdt - , Ludwig Maximilian University of Munich (Author)
  • Kathryn J Moore - , New York University (Author)

Abstract

The human genome encodes thousands of long non-coding RNAs (lncRNAs), the majority of which are poorly conserved and uncharacterized. Here we identify a primate-specific lncRNA (CHROME), elevated in the plasma and atherosclerotic plaques of individuals with coronary artery disease, that regulates cellular and systemic cholesterol homeostasis. LncRNA CHROME expression is influenced by dietary and cellular cholesterol via the sterol-activated liver X receptor transcription factors, which control genes mediating responses to cholesterol overload. Using gain- and loss-of-function approaches, we show that CHROME promotes cholesterol efflux and 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 levels of miR-27b, miR-33a, miR-33b and miR-128, thereby reducing expression of their overlapping target gene networks and associated biologic functions. In particular, cells lacking 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 non-coding RNA circuitry controlling cholesterol homeostasis in humans.

Details

Original languageEnglish
Pages (from-to)98-110
Number of pages13
JournalNature metabolism
Volume1
Issue number1
Publication statusPublished - Jan 2019
Peer-reviewedYes
Externally publishedYes

External IDs

PubMedCentral PMC6691505
Scopus 85070950057

Keywords

Sustainable Development Goals

Keywords

  • Animals, Atherosclerosis/genetics, Cholesterol/metabolism, Hepatocytes/metabolism, Homeostasis, Humans, Lipid Metabolism, Liver X Receptors/metabolism, MicroRNAs/genetics, Primates/genetics, RNA, Long Noncoding/genetics